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Zoicas I, Mühle C, von Hörsten S, Plank AC, Kornhuber J. Sitagliptin as a therapeutic approach for social anxiety disorder: the role of DPP4 and NPY in modulating social fear and comorbid depressive-like behavior in mice. Neuropsychopharmacology 2025:10.1038/s41386-025-02146-8. [PMID: 40490517 DOI: 10.1038/s41386-025-02146-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 05/26/2025] [Accepted: 05/30/2025] [Indexed: 06/11/2025]
Abstract
We have previously shown that neuropeptide Y (NPY) reduces social fear in an animal model that closely mimics the key behavioral symptoms of social anxiety disorder (SAD). Since NPY cannot yet be routinely administered to patients, we investigated the effects of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor approved for the treatment of type 2 diabetes mellitus, on social fear and comorbid depression in mice. In addition to its well-known effects on glucose metabolism, sitagliptin also prevents the degradation of NPY, thereby increasing its concentration in the blood and the brain. We show that sitagliptin administration via drinking water (50 and 100 mg/kg/day, for 4 weeks) not only reduced social fear but also prevented the onset of comorbid depressive-like behavior in outbred CD1 mice. A similar phenotype was observed in homozygous DPP4-deficient mice, emphasizing the role of DPP4 in regulating these behaviors. However, in NPY-deficient mice, sitagliptin showed reduced efficacy, suggesting that NPY plays an important role in mediating the effects of sitagliptin on social fear and comorbid depression. These findings have important clinical implications, indicating that early intervention with sitagliptin could be an effective strategy for treating SAD, alleviating both core symptoms and reducing the risk of developing comorbid mood disorders that often complicate treatment outcomes.
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Affiliation(s)
- Iulia Zoicas
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany.
| | - Christiane Mühle
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany
| | - Stephan von Hörsten
- Department of Experimental Therapy, Preclinical Experimental Center, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Palmsanlage 5, 91054, Erlangen, Germany
| | - Anne-Christine Plank
- Department of Experimental Therapy, Preclinical Experimental Center, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Palmsanlage 5, 91054, Erlangen, Germany
- Department of Child and Adolescent Mental Health, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany
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Zoicas I, von Hörsten S, Plank AC, Kornhuber J. Dipeptidyl peptidase-4 inhibitors enhance memory retention via neuropeptide Y. Eur J Pharmacol 2025; 996:177556. [PMID: 40139422 DOI: 10.1016/j.ejphar.2025.177556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 03/20/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
We have previously shown that neuropeptide Y (NPY) prolongs the retention of memory in the object discrimination test in mice. In this study, we investigated the potential memory-enhancing effects of dipeptidyl peptidase-4 (DPP4) inhibitors, commonly referred to as gliptins, which are known to prevent the degradation of NPY, thereby increasing its concentration. We show that administration of sitagliptin (50 and 100 mg/kg/day) and linagliptin (5 and 10 mg/kg/day) via the drinking water facilitates the retention of object memory in male CD1 mice, extending memory retention to time points when control mice no longer retain memory. Similar to gliptin-treated mice, male and female homozygous and heterozygous DPP4 deficient mice displayed intact object memory at time points when wild-type littermates showed no memory. Sitagliptin treatment, however, did not facilitate the retention of memory in male and female homozygous NPY deficient mice, indicating that NPY is essential for the memory-enhancing effects of sitagliptin. These results indicate that sitagliptin exerts memory-enhancing effects through an NPY-dependent mechanism and highlight the potential of gliptins as cognitive enhancers in healthy individuals.
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Affiliation(s)
- Iulia Zoicas
- Department of Psychiatry and Psychotherapy, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.
| | - Stephan von Hörsten
- Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Palmsanlage 5, 91054, Erlangen, Germany.
| | - Anne-Christine Plank
- Department of Experimental Therapy, Preclinical Experimental Center, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Palmsanlage 5, 91054, Erlangen, Germany.
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.
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Loera-Lopez AL, Lord MN, Noble EE. Astrocytes of the hippocampus and responses to periprandial neuroendocrine hormones. Physiol Behav 2025; 295:114913. [PMID: 40209869 PMCID: PMC12066093 DOI: 10.1016/j.physbeh.2025.114913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 03/15/2025] [Accepted: 04/08/2025] [Indexed: 04/12/2025]
Abstract
Astrocytes have risen as stars in the field of energy homeostasis and neurocognitive function, acting as a bridge of communication between the periphery and the brain, providing metabolic support, signaling via gliotransmitters, and altering synaptic communication. Dietary factors and energy state have a profound influence on hippocampal function, and the hippocampus is critical for appropriate behavioral responses associated with feeding and internal hunger cues (being in the fasted or full state), but how the hippocampus senses periprandial status and is impacted by diet is largely unknown. Periprandial hormones act within the hippocampus to modulate processes involved in hippocampal-dependent learning and memory function and astrocytes likely play an important role in modulating this signaling. In addition to periprandial hormones, astrocytes are positioned to respond to changes in circulating nutrients like glucose. Here, we review literature investigating how astrocytes mediate changes in hippocampal function, highlighting astrocyte location, morphology, and function in the context of integrating glucose metabolism, neuroendocrine hormone action, and/or cognitive function in the hippocampus. Specifically, we discuss research findings on the effects of insulin, ghrelin, leptin, and GLP-1 on glucose homeostasis, neural activity, astrocyte function, and behavior in the hippocampus. Because obesogenic diets impact neuroendocrine hormones, astrocytes, and cognitive function, we also discuss the effects of diet and diet-induced obesity on these parameters.
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Affiliation(s)
- Ana L Loera-Lopez
- Neuroscience Graduate Program, University of Georgia, Athens, GA, 30606, USA; Department of Nutritional Sciences, University of Georgia, Athens, GA, 30606, USA
| | - Magen N Lord
- Department of Nutritional Sciences, University of Georgia, Athens, GA, 30606, USA
| | - Emily E Noble
- Neuroscience Graduate Program, University of Georgia, Athens, GA, 30606, USA; Department of Nutritional Sciences, University of Georgia, Athens, GA, 30606, USA.
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Ye XW, Zhang HX, Li Q, Li CS, Zhao CJ, Xia LJ, Ren HM, Wang XX, Yang C, Wang YJ, Jiang SL, Xu XF, Li XR. Scientometric analysis and historical review of diabetic encephalopathy research: Trends and hotspots (2004-2023). World J Diabetes 2025; 16:91200. [DOI: 10.4239/wjd.v16.i5.91200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 12/18/2024] [Accepted: 02/20/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Diabetic encephalopathy (DE) is a common and serious complication of diabetes that can cause death in many patients and significantly affects the lives of individuals and society. Multiple studies investigating the pathogenesis of DE have been reported. However, few studies have focused on scientometric analysis of DE.
AIM To analyze literature on DE using scientometrics to provide a comprehensive picture of research directions and progress in this field.
METHODS We reviewed studies on DE or cognitive impairment published between 2004 and 2023. The latter were used to identify the most frequent keywords in the keyword analysis and explore the hotspots and trends of DE.
RESULTS Scientometric analysis revealed 1308 research papers on DE, a number that increased annually over the past 20 years, and that the primary topics explored were domain distribution, knowledge structure, evolution, and emergence of research topics related to DE. The inducing factors, comorbidities, pathogenesis, treatment, and animal models of DE help clarify its occurrence, development, and treatment. An increasing number of studies on DE may be a result of the recent increase in patients with diabetes, unhealthy lifestyles, and unhealthy eating habits, which have aggravated the incidence of this disease.
CONCLUSION We identified the main inducing factors and comorbidities of DE, though other complex factors undoubtedly increase social and economic burdens. These findings provide vital references for future studies.
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Affiliation(s)
- Xian-Wen Ye
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, Jiangxi Province, China
| | - Hai-Xia Zhang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Qian Li
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Chun-Shuai Li
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang 330004, Jiangxi Province, China
| | - Chong-Jun Zhao
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Liang-Jing Xia
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Hong-Min Ren
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xu-Xing Wang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Chao Yang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Yu-Jie Wang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Shui-Lan Jiang
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xin-Fang Xu
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
| | - Xiang-Ri Li
- Traditional Chinese Medicine Processing Technology Inheritance Base of the National Administration of Traditional Chinese Medicine/Beijing Key Laboratory for Quality Evaluation of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
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Pattanaik S, Prusty SK, Sahu PK. Exploring DPP IV inhibitors for Alzheimer's disease: Bridging diabetes and neurodegeneration. Brain Res 2025; 1848:149342. [PMID: 39566568 DOI: 10.1016/j.brainres.2024.149342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/03/2024] [Accepted: 11/16/2024] [Indexed: 11/22/2024]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neurofibrillary tangles (NFTs), senile plaques from Aβ deposits, neuronal inflammation, oxidative stress, and impaired neuronal transmission involving acetylcholine and glutamate. Diabetes patients are at a higher risk of developing AD-like pathology due to shared pathological and molecular mechanisms, including insulin resistance, oxidative stress, formation of advanced glycation end products (AGEs), and overactive immune systems. Current treatments of AD typically address only one aspect of the disease, rather than treating it as a multifactorial process. Targeting cerebral glucose-insulin metabolism has emerged as a promising strategy for AD management. Numerous studies show positive correlations between anti-diabetic drugs and AD management. Among these, DPP IV inhibitors have demonstrated significant therapeutic benefits against AD in experimental settings. DPP IV inhibitors have been shown to significantly reduce Aβ oligomerization, phosphorylated tau (p-tau), oxidative stress, and inflammatory markers, presenting a potentially effective approach for targeting AD-like pathology. Although preclinical data are promising, clinical trials are needed to validate these findings and establish the safety and efficacy of DPP IV inhibitors as a therapeutic intervention for AD. This could represent a novel approach for addressing both the metabolic and neurodegenerative aspects of AD.
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Affiliation(s)
- Swagata Pattanaik
- Department of Pharmacology, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar 751003, Odisha, India
| | - Shakti Ketan Prusty
- Department of Pharmacology, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar 751003, Odisha, India
| | - Pratap Kumar Sahu
- Department of Pharmacology, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Bhubaneswar 751003, Odisha, India.
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Yu SJ, Wang Y, Shen H, Bae EK, Li Y, Sambamurti K, Tones MA, Zaleska MM, Hoffer BJ, Greig NH. DPP-4 inhibitors sitagliptin and PF-00734,200 mitigate dopaminergic neurodegeneration, neuroinflammation and behavioral impairment in the rat 6-OHDA model of Parkinson's disease. GeroScience 2024; 46:4349-4371. [PMID: 38563864 PMCID: PMC11336009 DOI: 10.1007/s11357-024-01116-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 02/28/2024] [Indexed: 04/04/2024] Open
Abstract
Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70-80% plasma and 20-30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD.
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Affiliation(s)
- Seong-Jin Yu
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 35053, Taiwan
| | - Yun Wang
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 35053, Taiwan.
- National Institute On Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA.
| | - Hui Shen
- National Institute On Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Eun-Kyung Bae
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, 35053, Taiwan
| | - Yazhou Li
- National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Kumar Sambamurti
- Department of Neurosciences, the Medical University of South Carolina, Charleston, SC, 29425, USA
| | | | | | - Barry J Hoffer
- Department of Neurosurgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Nigel H Greig
- National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA.
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Li Y, Vaughan KL, Wang Y, Yu SJ, Bae EK, Tamargo IA, Kopp KO, Tweedie D, Chiang CC, Schmidt KT, Lahiri DK, Tones MA, Zaleska MM, Hoffer BJ, Mattison JA, Greig NH. Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders. GeroScience 2024; 46:4397-4414. [PMID: 38532069 PMCID: PMC11335710 DOI: 10.1007/s11357-024-01120-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Accepted: 03/01/2024] [Indexed: 03/28/2024] Open
Abstract
The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor.
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Affiliation(s)
- Yazhou Li
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Kelli L Vaughan
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Yun Wang
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, 35053
| | - Seong-Jin Yu
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, 35053
| | - Eun-Kyung Bae
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan, 35053
| | - Ian A Tamargo
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Katherine O Kopp
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - David Tweedie
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Cheng-Chuan Chiang
- Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Keith T Schmidt
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Debomoy K Lahiri
- Departments of Psychiatry and Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | | | | | - Barry J Hoffer
- Department of Neurosurgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, 44106, USA
| | - Julie A Mattison
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA
| | - Nigel H Greig
- Translational Gerontology Branch, National Institute On Aging, Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA.
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Huang KH, Yang Y, Gau SY, Tsai TH, Lee CY. Association between dipeptidyl peptidase-4 inhibitor use and risk of Parkinson's disease among patients with diabetes mellitus: a retrospective cohort study. Aging (Albany NY) 2024; 16:11994-12007. [PMID: 39177655 PMCID: PMC11386917 DOI: 10.18632/aging.206074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 07/11/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND How a person's Parkinson disease (PD) risk is affected by dipeptidyl peptidase-4 (DPP-4) inhibitors remains unclear. We evaluated the association of PD risk with use of these inhibitors in individuals diagnosed as having diabetes mellitus (DM). METHODS Individuals diagnosed as having new-onset DM were enrolled into the case group and comparison group, comprising patients who received a DPP-4 inhibitor and a sulfonylurea, respectively. These groups were matched through propensity score matching on the basis of income level, gender, urbanization level, enrollment year, age, and diabetes complications severity index score. The case group was divided into subgroups on the basis of whether they had a cumulative defined daily dose (cDDD) of <75, 75-150, or >150. The DPP-4 inhibitor-PD risk association was evaluated through a Cox proportional hazards model. The Bonferroni adjustment test was employed to adjust P-values and reduce the false positive rate. RESULTS Compared with those in the comparison group (treatment with a sulfonylurea), patients with a DPP-4 inhibitor cDDD of >150 had a hazard ratio (HR) of 1.30 for PD development (95% confidence interval [CI]: 0.97-1.73; adjusted P = .263); the HRs for patients with a cDDD of <75 or 75-150 were 0.95 (95% CI: 0.71-1.27; adjusted P = .886) and 1.06 (95% CI: 0.75-1.50; adjusted P = .886), respectively. We noted nonsignificant differences regarding the associations between the use of the various DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) and PD risk after adjustment for any individual inhibitor (adjusted P > .05). CONCLUSIONS DPP-4 inhibitors were discovered in this study to not be associated with increased PD risk. This result was confirmed when the analysis was conducted individually for the 4 investigated DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and vildagliptin).
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Affiliation(s)
- Kuang-Hua Huang
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan
| | - Yih Yang
- Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan
| | - Shuo-Yan Gau
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Tung-Han Tsai
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan
| | - Chien-Ying Lee
- Department of Pharmacology, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
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Zhuge F, Zheng L, Pan Y, Ni L, Fu Z, Shi J, Ni Y. DPP-4 inhibition by linagliptin ameliorates age-related mild cognitive impairment by regulating microglia polarization in mice. Exp Neurol 2024; 373:114689. [PMID: 38199510 DOI: 10.1016/j.expneurol.2024.114689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 12/29/2023] [Accepted: 01/06/2024] [Indexed: 01/12/2024]
Abstract
Extensive preclinical evidence demonstrates a causative link between insulin signaling dysfunction and the pathogenesis of Alzheimer's disease (AD), and diabetic drugs may represent a promising approach to fighting AD. However, it remains to be determined which antidiabetic drugs are more effective in preventing cognitive impairment. Thus, the present study investigated the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on cognitive impairment in middle-aged mice by comparing it with the effect of metformin. We found that DPP-4 activity increased in the hippocampus of middle-aged mice, and DPP-4 was mainly expressed by microglia rather than astrocytes and oligodendrocytes. DPP-4 directly regulated M1/M2 microglia polarization following LPS or IL-4 stimulation, while DPP-4 inhibitor, linagliptin, suppressed M1-polarized activation and induced M2-polarized activation. Both linagliptin and metformin enhanced cognitive ability, increased hippocampal synaptic plasticity and neurogenesis, and decreased age-related oxidative stress and inflammation by regulating microglia polarization in the hippocampus of middle-aged mice. The combination of linagliptin and metformin showed a maximum protective effect compared to the individual drugs alone. Loss of macrophage inflammatory protein-1α (MIP-1α), a DPP-4 substrate, abrogated the cognitive protection and anti-inflammation effects of linagliptin. Therefore, the current investigation exhibits a potential utility for DPP-4 inhibition in attenuating microglia-mediated inflammation and preventing mild cognitive impairment (MCI) in middle-aged mice, and the effect was partly mediated by MIP-1α.
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Affiliation(s)
- Fen Zhuge
- Institute of Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Liujie Zheng
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Yuxiang Pan
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Liyang Ni
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan
| | - Zhengwei Fu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China
| | - Junping Shi
- Department of Infectious Disease, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Yinhua Ni
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, China.
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Pereira VM, Pradhanang S, Prather JF, Nair S. Role of Metalloproteinases in Diabetes-associated Mild Cognitive Impairment. Curr Neuropharmacol 2024; 23:58-74. [PMID: 38963109 PMCID: PMC11519823 DOI: 10.2174/1570159x22666240517090855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/24/2024] [Accepted: 02/14/2024] [Indexed: 07/05/2024] Open
Abstract
Diabetes has been linked to an increased risk of mild cognitive impairment (MCI), a condition characterized by a subtle cognitive decline that may precede the development of dementia. The underlying mechanisms connecting diabetes and MCI involve complex interactions between metabolic dysregulation, inflammation, and neurodegeneration. A critical mechanism implicated in diabetes and MCI is the activation of inflammatory pathways. Chronic low-grade inflammation, as observed in diabetes, can lead to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and interferon-gamma (IFNγ), each of which can exacerbate neuroinflammation and contribute to cognitive decline. A crucial enzyme involved in regulating inflammation is ADAM17, a disintegrin, and metalloproteinase, which can cleave and release TNF-α from its membrane-bound precursor and cause it to become activated. These processes, in turn, activate additional inflammation-related pathways, such as AKT, NF-κB, NLP3, MAPK, and JAK-STAT pathways. Recent research has provided novel insights into the role of ADAM17 in diabetes and neurodegenerative diseases. ADAM17 is upregulated in both diabetes and Alzheimer's disease, suggesting a shared mechanism and implicating inflammation as a possible contributor to much broader forms of pathology and pointing to a possible link between inflammation and the emergence of MCI. This review provides an overview of the different roles of ADAM17 in diabetes-associated mild cognitive impairment diseases. It identifies mechanistic connections through which ADAM17 and associated pathways may influence the emergence of mild cognitive impairment.
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Affiliation(s)
- Vitoria Mattos Pereira
- School of Pharmacy, College of Health Sciences, Biomedical Sciences, Interdisciplinary Graduate Program, University of Wyoming, Laramie, WY 82071, USA
| | - Suyasha Pradhanang
- School of Pharmacy, College of Health Sciences, Biomedical Sciences, Interdisciplinary Graduate Program, University of Wyoming, Laramie, WY 82071, USA
| | - Jonathan F. Prather
- Department of Zoology and Physiology, Program in Neuroscience, University of Wyoming, Laramie, WY 82071, USA
| | - Sreejayan Nair
- School of Pharmacy, College of Health Sciences, Biomedical Sciences, Interdisciplinary Graduate Program, University of Wyoming, Laramie, WY 82071, USA
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11
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Meng J, Yan R, Zhang C, Bai X, Yang X, Yang Y, Feng T, Liu X. Dipeptidyl peptidase-4 inhibitors alleviate cognitive dysfunction in type 2 diabetes mellitus. Lipids Health Dis 2023; 22:219. [PMID: 38082288 PMCID: PMC10712048 DOI: 10.1186/s12944-023-01985-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 12/04/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2DM) are commonly at high risk for developing cognitive dysfunction. Antidiabetic agents might be repurposed for targeting cognitive dysfunction in addition to modulation on glucose homeostasis. This study aimed to evaluate the impact of dipeptidyl peptidase-4 inhibitors (DPP-4i) on cognitive function in T2DM. METHODS PubMed, Embase, Cochrane Library and Web of Science were systematically searched from inception to September 30, 2023. Weighted mean differences were calculated using the Mantel-Haenszel (M-H) fixed or random effects model based on the degree of heterogeneity among studies. Heterogeneity was evaluated using a Chi-squared test and quantified with Higgins I2. Sensitivity analysis was performed with the leave-one-out method, and publication bias was evaluated according to Begg's and Egger's tests. RESULTS Six clinical trials involving 5,178 participants were included in the pooled analysis. Administration of DPP-4i generally correlated with an increase of Mini-Mental State Examination (MMSE) scores (1.09, 95% CI: 0.22 to 1.96). DPP-4i alleviated cognitive impairment in the copying skill subdomain of MMSE (0.26, 95% CI: 0.12 to 0.40). Treatment with DPP-4i also resulted in an increase of Instrumental Activities of Daily Living (IADL) scores (0.82, 95% CI: 0.30 to 1.34). However, DPP-4i produced no significant effects on Barthel Activities of Daily Living (BADL) scores (0.37, 95% CI: -1.26 to 1.99) or other test scores. CONCLUSIONS DPP-4i treatment favourably improved cognitive function in patients with T2DM. Further trials with larger samples should be performed to confirm these estimates and investigate the association of different DPP-4i with cognitive function among diabetic patients. TRIAL REGISTRATION IN PROSPERO CRD42023430873.
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Affiliation(s)
- Jie Meng
- Department of Pathology, Beijing TongRen Hospital, Capital Medical University, Beijing, China
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Rui Yan
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chen Zhang
- National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xueyan Bai
- Department of Hemotology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xingsheng Yang
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yu Yang
- Department of Cardiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Tao Feng
- Center for Movement Disorders, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
- National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
| | - Xin Liu
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
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12
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Pradhan SP, Sahu PK, Behera A. New insights toward molecular and nanotechnological approaches to antidiabetic agents for Alzheimer's disease. Mol Cell Biochem 2023; 478:2739-2762. [PMID: 36949264 DOI: 10.1007/s11010-023-04696-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 02/27/2023] [Indexed: 03/24/2023]
Abstract
Alzheimer's disease (AD) is a chronic neurodegenerative disorder affecting a major class of silver citizens. The disorder shares a mutual relationship on account of its cellular and molecular pathophysiology with type-II diabetes mellitus (DM). Chronic DM increases the risk for AD. Emerging evidence recommended that resistance in insulin production develops cognitive dysfunction, which generally leads to AD. Repurposing of antidiabetic drugs can be effective in preventing and treatment of the neurodegenerative disorder. Limitations of antidiabetic drugs restrict the repurposing of the drugs for other disorders. Therefore, nanotechnological intervention plays a significant role in the treatment of neurological disorders. In this review, we discuss the common cellular and molecular pathophysiologies between AD and type-II DM, the relevance of in vivo models of type II DM in the study of AD, and the repurposing of antidiabetic drugs and the nanodelivery systems of antidiabetic drugs against AD.
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Affiliation(s)
- Sweta Priyadarshini Pradhan
- School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Campus-II, Kalinga Nagar, Bhubaneswar, Odisha, India
| | - Pratap Kumar Sahu
- School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Campus-II, Kalinga Nagar, Bhubaneswar, Odisha, India
| | - Anindita Behera
- School of Pharmaceutical Sciences, Siksha 'O' Anusandhan Deemed to be University, Campus-II, Kalinga Nagar, Bhubaneswar, Odisha, India.
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13
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Hung YW, Lu GL, Chen HH, Tung HH, Lee SL. Gliptins normalize posttraumatic hippocampal neurogenesis and restore cognitive function after controlled cortical impact on sensorimotor cortex. Biomed Pharmacother 2023; 165:115270. [PMID: 37544280 DOI: 10.1016/j.biopha.2023.115270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/31/2023] [Accepted: 07/31/2023] [Indexed: 08/08/2023] Open
Abstract
Traumatic brain injury (TBI) often leads to long-term neurocognitive dysfunctions. Adult neurogenesis in the hippocampal dentate gyrus (DG) serves critical functions in cognition but can be disrupted by brain injury and insult in serval forms. In the present study, we explore the cellular and molecular targets of DPP-4 inhibitors (or gliptins) as related to hippocampal function and TBI cognitive sequelae. Two structurally different gliptins, sitagliptin and vildagliptin, were examined using a controlled cortical impact (CCI) model of moderate TBI in mice. Sensorimotor CCI, although distal from the hippocampus, impaired hippocampal-dependent cognition without obvious hippocampal tissue destruction. Neurogenic cell proliferation in the DG was increased accompanied by large numbers of reactive astrocyte. Increased numbers of immature granule cells with abnormal dendritic outgrowth were ectopically localized in the outer granule cell layer (GCL) and hilus. Long-term potentiation of dentate immature granule cells was also impaired. Both sitagliptin and vildagliptin attenuated the CCI-induced ectopic migration of doublecortin-positive immature neurons into the outer GCL and hilus, restored the normal dendritic branching pattern of the immature neurons and prevented astrocyte reactivation. Both gliptins prevented loss of normal synaptic integration in the DG after sensorimotor CCI and improved cognitive behavior. Sensorimotor cortical injury thus results in an abnormal neurogenesis pattern and astrocyte reactivation in the distal hippocampus which appears to contribute to the development of cognitive dysfunction after TBI. DPP-4 inhibitors prevent astrocyte reactivation, normalize the posttraumatic hippocampal neurogenesis and help to maintain normal electrophysiology in the DG with positive behavioral effect in a mouse model.
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Affiliation(s)
- Yu-Wen Hung
- Institute of Cellular and Systems Medicine, Taiwan, R.O.C
| | - Guan-Ling Lu
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan Town, Maioli County, Taiwan, R.O.C
| | - Hwei-Hsien Chen
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan Town, Maioli County, Taiwan, R.O.C
| | - Hsiu-Hui Tung
- Institute of Cellular and Systems Medicine, Taiwan, R.O.C
| | - Sheau-Ling Lee
- Institute of Cellular and Systems Medicine, Taiwan, R.O.C; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C; Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, R.O.C.
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14
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Ruiz-Pozo VA, Tamayo-Trujillo R, Cadena-Ullauri S, Frias-Toral E, Guevara-Ramírez P, Paz-Cruz E, Chapela S, Montalván M, Morales-López T, Simancas-Racines D, Zambrano AK. The Molecular Mechanisms of the Relationship between Insulin Resistance and Parkinson's Disease Pathogenesis. Nutrients 2023; 15:3585. [PMID: 37630775 PMCID: PMC10458139 DOI: 10.3390/nu15163585] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 08/04/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Parkinson's disease (PD) is a degenerative condition resulting from the loss of dopaminergic neurons. This neuronal loss leads to motor and non-motor neurological symptoms. Most PD cases are idiopathic, and no cure is available. Recently, it has been proposed that insulin resistance (IR) could be a central factor in PD development. IR has been associated with PD neuropathological features like α-synuclein aggregation, dopaminergic neuronal loss, neuroinflammation, mitochondrial dysfunction, and autophagy. These features are related to impaired neurological metabolism, neuronal death, and the aggravation of PD symptoms. Moreover, pharmacological options that involve insulin signaling improvement and dopaminergic and non-dopaminergic strategies have been under development. These drugs could prevent the metabolic pathways involved in neuronal damage. All these approaches could improve PD outcomes. Also, new biomarker identification may allow for an earlier PD diagnosis in high-risk individuals. This review describes the main pathways implicated in PD development involving IR. Also, it presents several therapeutic options that are directed at insulin signaling improvement and could be used in PD treatment. The understanding of IR molecular mechanisms involved in neurodegenerative development could enhance PD therapeutic options and diagnosis.
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Affiliation(s)
- Viviana A Ruiz-Pozo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador
| | - Rafael Tamayo-Trujillo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador
| | - Santiago Cadena-Ullauri
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador
| | - Evelyn Frias-Toral
- School of Medicine, Universidad Católica Santiago de Guayaquil, Guayaquil 090615, Ecuador
| | - Patricia Guevara-Ramírez
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador
| | - Elius Paz-Cruz
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador
| | - Sebastián Chapela
- Departamento de Bioquímica, Facultad de Ciencias Médicas, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires C1121ABE, Argentina
- Equipo de Soporte Nutricional, Hospital Británico de Buenos Aires, Ciudad Autónoma de Buenos Aires C1280AEB, Argentina
| | - Martha Montalván
- School of Medicine, Universidad Espíritu Santo, Samborondón 091952, Ecuador
| | - Tania Morales-López
- Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador
| | - Daniel Simancas-Racines
- Centro de Investigación de Salud Pública y Epidemiología Clínica (CISPEC), Universidad UTE, Quito 170527, Ecuador
| | - Ana Karina Zambrano
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito 170527, Ecuador
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15
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Kuthati Y, Rao VN, Huang WH, Busa P, Wong CS. Teneligliptin Co-Infusion Alleviates Morphine Tolerance by Inhibition of Spinal Microglial Cell Activation in Streptozotocin-Induced Diabetic Rats. Antioxidants (Basel) 2023; 12:1478. [PMID: 37508016 PMCID: PMC10376493 DOI: 10.3390/antiox12071478] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/17/2023] [Accepted: 07/22/2023] [Indexed: 07/30/2023] Open
Abstract
Morphine (MOR) is a commonly prescribed drug for the treatment of moderate to severe diabetic neuropathic pain (DNP). However, long-term MOR treatment is limited by morphine analgesic tolerance (MAT). The activation of microglial cells and the release of glia-derived proinflammatory cytokines are known to play an important role in the development of MAT. In this study, we aimed to investigate the effects of the dipeptidyl peptidase-4 inhibitor (DPP-4i) teneligliptin (TEN) on MOR-induced microglial cell activation and MAT in DNP rats. DNP was induced in four groups of male Wistar rats through a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg, freshly dissolved in 5 mmol/L citrate buffer, pH 4.5). Sham rats were administered with the vehicle. Seven days after STZ injection, all rats were implanted with an intrathecal (i.t) catheter connected to a mini-osmotic pump, divided into five groups, and infused with the following combinations: sham + saline (1 µL/h, i.t), DNP + saline (1 µL/h, i.t), DNP + MOR (15 µg/h, i.t), DNP + TEN (2 µg/h, i.t), and DNP + MOR (15 µg/h, i.t) + TEN (2 µg/h, i.t) for 7 days at a rate of 1 μL/h. The MAT was confirmed through the measurement of mechanical paw withdrawal threshold and tail-flick tests. The mRNA expression of neuroprotective proteins nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1) in the dorsal horn was evaluated by quantitative PCR (qPCR). Microglial cell activation and mononucleate cell infiltration in the spinal cord dorsal horn were assessed by immunofluorescence assay (IFA) and Western blotting (WB). The results showed that co-infusion of TEN with MOR significantly attenuated MAT in DNP rats through the restoration of neuroprotective proteins Nrf2 and HO-1 and suppression of microglial cell activation in the dorsal horn. Though TEN at a dose of 2 μg has mild antinociceptive effects, it is highly effective in limiting MAT.
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Affiliation(s)
- Yaswanth Kuthati
- Department of Anesthesiology, Cathy General Hospital, Taipei 106, Taiwan
| | - Vaikar Navakanth Rao
- PhD Program in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien 970, Taiwan
| | - Wei-Hsiu Huang
- Department of Anesthesiology, Cathy General Hospital, Taipei 106, Taiwan
| | - Prabhakar Busa
- Department of Anesthesiology, Cathy General Hospital, Taipei 106, Taiwan
| | - Chih-Shung Wong
- Department of Anesthesiology, Cathy General Hospital, Taipei 106, Taiwan
- National Defense Medical Center, Institute of Medical Sciences, Taipei 114, Taiwan
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16
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Alrouji M, Al-Kuraishy HM, Al-Buhadily AK, Al-Gareeb AI, Elekhnawy E, Batiha GES. DPP-4 inhibitors and type 2 diabetes mellitus in Parkinson's disease: a mutual relationship. Pharmacol Rep 2023:10.1007/s43440-023-00500-5. [PMID: 37269487 DOI: 10.1007/s43440-023-00500-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/17/2023] [Accepted: 05/19/2023] [Indexed: 06/05/2023]
Abstract
Parkinson's disease (PD) usually occurs due to the degeneration of dopaminergic neurons in the substantia nigra (SN). Management of PD is restricted to symptomatic improvement. Consequently, a novel treatment for managing motor and non-motor symptoms in PD is necessary. Abundant findings support the protection of dipeptidyl peptidase 4 (DPP-4) inhibitors in PD. Consequently, this study aims to reveal the mechanism of DPP-4 inhibitors in managing PD. DPP-4 inhibitors are oral anti-diabetic agents approved for managing type 2 diabetes mellitus (T2DM). T2DM is linked with an increased chance of the occurrence of PD. Extended usage of DPP-4 inhibitors in T2DM patients may attenuate the development of PD by inhibiting inflammatory and apoptotic pathways. Thus, DPP-4 inhibitors like sitagliptin could be a promising treatment against PD neuropathology via anti-inflammatory, antioxidant, and anti-apoptotic impacts. DPP-4 inhibitors, by increasing endogenous GLP-1, can also reduce memory impairment in PD. In conclusion, the direct effects of DPP-4 inhibitors or indirect effects through increasing circulating GLP-1 levels could be an effective therapeutic strategy in treating PD patients through modulation of neuroinflammation, oxidative stress, mitochondrial dysfunction, and neurogenesis.
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Affiliation(s)
- Mohammed Alrouji
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Shaqra University, Shaqra, 11961, Saudi Arabia
| | - Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
| | - Ali K Al-Buhadily
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
| | - Engy Elekhnawy
- Pharmaceutical Microbiology Department, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt.
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AL Beheira, Egypt.
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17
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Li Z, Xiang J, Mei S, Wu Y, Xu Y. The effect of PINK1/Parkin pathway on glucose homeostasis imbalance induced by tacrolimus in mouse livers. Heliyon 2023; 9:e15536. [PMID: 37151651 PMCID: PMC10161719 DOI: 10.1016/j.heliyon.2023.e15536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Revised: 04/05/2023] [Accepted: 04/13/2023] [Indexed: 05/09/2023] Open
Abstract
Treatment using the immunosuppressive drug tacrolimus (TAC) is related to new-onset diabetes after transplantation (NODAT). Previous studies focused mainly on islet β cells in the diabetogenic effect of TAC. Herein, we revealed that NODAT was probably induced by TAC via hepatic insulin resistance. After daily injection of mice with TAC, a glucose metabolism disorder was induced. In addition, TAC decreased the mRNA and protein levels of insulin receptor substrate 2 (IRS2), glucose transporter type 2 (GLUT2), and the phosphorylation of protein kinase B beta (pAKT2), which indicated impaired hepatic insulin signaling. Furthermore, the PTEN-induced novel kinase 1(PINK1)/Parkin pathway was shown to have a key role in the TAC-induced imbalance of hepatic glucose homeostasis. Mechanistic investigations in human hepatic cell lines revealed that TAC stimulated PINK1/Parkin expression and inhibited the expression of insulin signaling related molecules (e.g., IRS2, GLUT2 and pAKT2). Knockdown of hepatic PINK1 regulated downstream molecules of the PINK1/Parkin pathway (GLUT2 and IRS2), which reversed TAC-induced insulin resistance. Thus, in the liver, PINK1/Parkin signaling plays an important role in the TAC-induced imbalance of glucose homeostasis. TAC-induced diabetes might be prevented using Targeted treatment.
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Affiliation(s)
- Zhiwei Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jie Xiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shengmin Mei
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yue Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yuan Xu
- Department of Orthopedics, Zhejiang Hospital, Hangzhou, Zhejiang, China
- Corresponding author. Department of Orthopedics, Zhejiang Hospital, No. 12 Lingyin Road, Hangzhou, Zhejiang 3100013, China.
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18
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Zhou H, Rao Z, Zhang Z, Zhou J. Function of the GABAergic System in Diabetic Encephalopathy. Cell Mol Neurobiol 2023; 43:605-619. [PMID: 35460435 PMCID: PMC11415196 DOI: 10.1007/s10571-022-01214-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 03/17/2022] [Indexed: 11/03/2022]
Abstract
Diabetes is a common metabolic disease characterized by loss of blood sugar control and a high rate of complications. γ-Aminobutyric acid (GABA) functions as the primary inhibitory neurotransmitter in the adult mammalian brain. The normal function of the GABAergic system is affected in diabetes. Herein, we summarize the role of the GABAergic system in diabetic cognitive dysfunction, diabetic blood sugar control disorders, diabetes-induced peripheral neuropathy, diabetic central nervous system damage, maintaining diabetic brain energy homeostasis, helping central control of blood sugar and attenuating neuronal oxidative stress damage. We show the key regulatory role of the GABAergic system in multiple comorbidities in patients with diabetes and hope that further studies elucidating the role of the GABAergic system will yield benefits for the treatment and prevention of comorbidities in patients with diabetes.
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Affiliation(s)
- Hongli Zhou
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China
| | - Zhili Rao
- Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, People's Republic of China
| | - Zuo Zhang
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China
| | - Jiyin Zhou
- National Drug Clinical Trial Institution, Second Affiliated Hospital, Army Medical University, Chongqing, 400037, People's Republic of China.
- Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, People's Republic of China.
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19
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You S, Bi Y, Miao M, Bao A, Du J, Xu T, Liu CF, Zhang Y, He J, Cao Y, Zhong C. Plasma sDPP4 (Soluble Dipeptidyl Peptidase-4) and Cognitive Impairment After Noncardioembolic Acute Ischemic Stroke. Stroke 2023; 54:113-121. [PMID: 36475470 DOI: 10.1161/strokeaha.122.040798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND DPP4 (dipeptidyl peptidase-4) inhibitors have been proven to promote neuronal regeneration, reverse the development of cognitive deficits. However, the association of circulating soluble form (sDPP4 [soluble DPP4]) with poststroke cognitive impairment (PSCI) is unclear. We aimed to investigate the association between plasma sDPP4 levels and PSCI in patients with ischemic stroke. METHODS A total of 600 noncardioembolic stroke patients were included based on a preplanned ancillary study from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). We used the Montreal Cognitive Assessment to evaluate cognitive function at 3 months follow-up after ischemic stroke. Binary logistic regression analyses were performed to investigate the association of plasma sDPP4 levels with subsequent PSCI. We further calculated integrated discrimination improvement and category-free net reclassification improvement to investigate the incremental prognostic effect of plasma sDPP4 beyond the basic model with conventional risk factors. RESULTS Plasma sDPP4 was inversely associated with PSCI after ischemic stroke, and the adjusted odds ratio (95% CI) for the highest versus lowest quartile of sDPP4 was 0.49 (0.29-0.81; P for trend=0.011). Each 1-SD increase of logarithm-transformed plasma sDPP4 concentration was associated with 17% (odds ratio, 0.83 [95% CI, 0.70-0.99]) lower risk of PSCI. Adding plasma sDPP4 to the basic model notably improved risk reclassification for PSCI, as shown by a category-free net reclassification improvement of 19.10% (95% CI, 2.52%-35.68%; P=0.03) and integrated discrimination improvement of 0.79% (95% CI, 0.13%-1.46%; P=0.02). CONCLUSIONS Higher plasma sDPP4 levels were associated with decreased risk of cognitive impairment after noncardioembolic ischemic stroke.
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Affiliation(s)
- Shoujiang You
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, China (S.Y., C.-F.L., Y.C.).,Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Yucong Bi
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Mengyuan Miao
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Anran Bao
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Jigang Du
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Tan Xu
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Chun-Feng Liu
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, China (S.Y., C.-F.L., Y.C.).,Institutes of Neuroscience, Soochow University, Suzhou, China (C.-F.L., Y.C.)
| | - Yonghong Zhang
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
| | - Jiang He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (J.H.)
| | - Yongjun Cao
- Department of Neurology and Suzhou Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, China (S.Y., C.-F.L., Y.C.).,Institutes of Neuroscience, Soochow University, Suzhou, China (C.-F.L., Y.C.)
| | - Chongke Zhong
- Department of Epidemiology, School of Public Health, Medical College of Soochow University, Suzhou, China (Y.B., M.M., A.B., J.D., T.X., Y.Z., C.Z.)
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20
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Steiner A, Owen BM, Bauer JP, Seanez L, Kwon S, Biddinger JE, Huffman R, Ayala JE, Nobis WP, Lewis AS. Glucagon-like peptide-1 receptor differentially controls mossy cell activity across the dentate gyrus longitudinal axis. Hippocampus 2022; 32:797-807. [PMID: 36063105 PMCID: PMC9675713 DOI: 10.1002/hipo.23469] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/27/2022] [Accepted: 08/18/2022] [Indexed: 01/07/2023]
Abstract
Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. Less well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through expression of its receptor, GLP-1R. RNA-seq demonstrated that most, though not all, Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r-ires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 μg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study adds to known MC activity modulators a neurohormonal mechanism that may preferentially affect ventral DG physiology and may potentially be targetable by several GLP-1R pharmacotherapies already in clinical use.
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Affiliation(s)
- Alex Steiner
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Benjamin M. Owen
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - James P. Bauer
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Leann Seanez
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sam Kwon
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jessica E. Biddinger
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Ragan Huffman
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Julio E. Ayala
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
- Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA
| | - William P. Nobis
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alan S. Lewis
- Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Addiction Research, Vanderbilt University, Nashville, TN, USA
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21
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Ferrari F, Moretti A, Villa RF. Incretin-based drugs as potential therapy for neurodegenerative diseases: current status and perspectives. Pharmacol Ther 2022; 239:108277. [DOI: 10.1016/j.pharmthera.2022.108277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 10/14/2022]
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22
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Guo J, Xu F, Xie Y, Chen B, Wang Y, Nie W, Zhou K, Zhou H, Xu B. Effect of Xuanwei Ham Proteins with Different Ripening Periods on Lipid Metabolism, Oxidative Stress and Gut Microbiota in Mice. Mol Nutr Food Res 2022; 66:e2101020. [DOI: 10.1002/mnfr.202101020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 06/19/2022] [Indexed: 11/12/2022]
Affiliation(s)
- Jie Guo
- School of Food and Biological Engineering Hefei University of Technology Hefei 230601 China
- Engineering Research Center of Bio‐process Ministry of Education Hefei University of Technology Hefei 230601 China
| | - Feiran Xu
- School of Food and Biological Engineering Hefei University of Technology Hefei 230601 China
- Engineering Research Center of Bio‐process Ministry of Education Hefei University of Technology Hefei 230601 China
- Anhui Qingsong Food Co., Ltd. No.28 Ningxi Road Hefei 231299 China
| | - Yong Xie
- School of Food and Biological Engineering Hefei University of Technology Hefei 230601 China
- Engineering Research Center of Bio‐process Ministry of Education Hefei University of Technology Hefei 230601 China
| | - Bo Chen
- School of Food and Biological Engineering Hefei University of Technology Hefei 230601 China
- Engineering Research Center of Bio‐process Ministry of Education Hefei University of Technology Hefei 230601 China
| | - Ying Wang
- School of Food and Biological Engineering Hefei University of Technology Hefei 230601 China
- Engineering Research Center of Bio‐process Ministry of Education Hefei University of Technology Hefei 230601 China
| | - Wen Nie
- School of Food and Biological Engineering Hefei University of Technology Hefei 230601 China
- Engineering Research Center of Bio‐process Ministry of Education Hefei University of Technology Hefei 230601 China
| | - Kai Zhou
- School of Food and Biological Engineering Hefei University of Technology Hefei 230601 China
- Engineering Research Center of Bio‐process Ministry of Education Hefei University of Technology Hefei 230601 China
| | - Hui Zhou
- School of Food and Biological Engineering Hefei University of Technology Hefei 230601 China
- Engineering Research Center of Bio‐process Ministry of Education Hefei University of Technology Hefei 230601 China
| | - Baocai Xu
- School of Food and Biological Engineering Hefei University of Technology Hefei 230601 China
- Engineering Research Center of Bio‐process Ministry of Education Hefei University of Technology Hefei 230601 China
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23
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Wei YD, Chen XX, Yang LJ, Gao XR, Xia QR, Qi CC, Ge JF. Resveratrol ameliorates learning and memory impairments induced by bilateral hippocampal injection of streptozotocin in mice. Neurochem Int 2022; 159:105385. [PMID: 35843421 DOI: 10.1016/j.neuint.2022.105385] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 06/15/2022] [Accepted: 06/27/2022] [Indexed: 01/10/2023]
Abstract
Resveratrol (RES) is a polyphenol with diverse beneficial pharmacological activities, and our previous results have demonstrated its neuroprotective potential. The purpose of this study was to investigate the therapeutic effect of RES in Alzheimer's disease (AD)-like behavioral dysfunction induced by streptozotocin (STZ) and explore it's potential mechanism of action. STZ was microinjected bilaterally into the dorsal hippocampus of C57BL/6J mice at a dose of 3 mg/kg, and RES was administered intragastrically at a dose of 25 mg/kg for 5 weeks. Neurobehavioral performance was observed, and serum concentrations of insulin and Nesfatin-1 were measured. Moreover, the protein expression of amyloid beta 1-42 (Aβ1-42), Tau, phosphorylated Tau (p-Tau) (Ser396), synaptic ras GTPase activation protein (SynGAP), postsynaptic density protein 95 (PSD95), synapsin-1, synaptogomin-1, and key molecules of the Wnt/β-catenin signaling pathway in the hippocampus and prefrontal cortex (PFC) were assessed. Finally, pathological damage to hippocampal tissue was examined by Nissl and immunofluorescence staining. The results showed that compared with the controls, bilateral hippocampal microinjections of STZ induced task-specific learning and memory impairments, as indicated by the disadvantaged performances in the novel object recognition test (NOR) and Morris water maze (MWM), but not the contextual fear conditioning test (CFC). Treatment with RES could improve these behavioral disadvantages. The serum concentrations of insulin and Nesfatin-1 in the model group were remarkably higher than those of the control group. In addition, protein expression of Aβ1-42, Tau, and p-Tau (Ser396) was increased but expression of SynGAP, PSD95, brain-derived neurotrophic factor (BDNF), and p-GSK-3β/GSK-3β were decreased in the hippocampus. Although the protein expression of BDNF and SynGAP was also markedly decreased in the PFC of the model mice, there was no significant difference among groups in the protein expression of PSD95, BDNF, synapsin-1, synaptogomin-1, and p-GSK-3β/GSK-3β. RES (25 mg/kg) reversed the enhanced insulin level, the abnormal protein expression of Aβ1-42, Tau, and p-Tau (Ser396) in the hippocampus and PFC, and the hippocampal protein expression of SynGAP, PSD95 and BDNF. In addition, RES reversed the STZ-induced decrease in the number of Nissl bodies and the increase in fluorescence intensity of IBA1 in the hippocampal CA1 region. These findings indicate that RES could ameliorate STZ-induced AD-like neuropathological injuries, the mechanism of which could be partly related to its regulation of BDNF expression and synaptic plasticity-associated proteins in the hippocampus.
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Affiliation(s)
- Ya-Dong Wei
- School of Pharmacy, Anhui Medical University, Hefei, China; Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Xing-Xing Chen
- School of Pharmacy, Anhui Medical University, Hefei, China; Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Long-Jun Yang
- Chaohu Clinical Medical College, Anhui Medical University, Hefei, China
| | - Xin-Ran Gao
- School of Pharmacy, Anhui Medical University, Hefei, China; Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
| | - Qing-Rong Xia
- Department of Pharmacy, Hefei Fourth People's Hospital, Hefei, China; Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China; Clinical Pharmacy, Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
| | - Cong-Cong Qi
- State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, And Department of Laboratory Animal Science, Fudan University, Shanghai, China.
| | - Jin-Fang Ge
- School of Pharmacy, Anhui Medical University, Hefei, China; Anhui Provincial Laboratory of Inflammatory and Immunity Disease, Anhui Institute of Innovative Drugs, Hefei, China; The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
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24
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Famurewa AC, Aja PM, Medewase JO, Abi I, Ogbonna OC, Ofor CC, Nwonuma CO, Asogwa NT, Erejuwa OO. Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Exhibits Antioxidant Mechanism for Abrogation of Cyclophosphamide-Induced Cardiac Damage and Oxidative Hepatorenal Toxicity in Rats. Drug Res (Stuttg) 2022; 72:396-403. [PMID: 35772725 DOI: 10.1055/a-1842-7596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Cyclophosphamide (CYP) is a potent DNA-interactive anticancer drug; however, its clinical drawbacks are chiefly associated with induction of oxidative multi-organ toxicity. Sitagliptin (STG) is an antidiabetic dipeptidyl peptidase-4 inhibitor drug with antioxidant efficacy. Herein, we have explored whether STG could abrogate the CYP-induced oxidative stress-mediated cardiac and hepatorenal toxicities in male rats. Sitagliptin (20 mg/kg, o.p) was administered to rats for 5 consecutive days against organ toxicities induced by CYP (200 mg/kg, i.p) on day 5 only. CYP induced marked injuries in the liver, kidney and heart underscored by prominent increases in serum activities of ALT, AST, LDH, creatine kinase and levels of urea, uric acid and creatinine, while albumin level significantly decreased compared to normal control rats. Further, CYP considerably reduced the activities of SOD, CAT, GPx, and levels of GSH, whereas MDA level increased significantly in comparison to control rats. These biochemical alterations were confirmed by multiple histopathological lesions in the tissues. Interestingly, the STG pretreatment abrogated the biochemical and histopathological changes induced by CYP. These results provide first evidence that repurposing STG may protect the liver, kidney and heart from the oxidative deterioration associated with CYP chemotherapy.
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Affiliation(s)
- Ademola C Famurewa
- Department of Medical Biochemistry, Faculty of Basic Medical Sciences, College of Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ikwo, Ebonyi State, Nigeria
| | - Patrick M Aja
- Department of Biochemistry, Faculty of Biological Sciences, Ebonyi State University, Abakaliki, Nigeria
| | - John O Medewase
- Department of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, Nigeria
| | - Innocent Abi
- Department of Physiology, Benue State University, Makurdi, Benue State, Nigeria
| | - Okoro C Ogbonna
- Department of Medical Biochemistry, School of Basic Medical Science, Federal University of Technology, Owerri, Imo State, Nigeria
| | - Casimir C Ofor
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Ebonyi State University, Abakaliki, Ebonyi State, Nigeria
| | - Charles O Nwonuma
- Department of Biochemistry, Landmark University, Omu-Aran, Kwara State, Nigeria
| | - Nnaemeka T Asogwa
- Central Research and Diagnostic Laboratory, Tanke, Ilorin, Kwara State, Nigeria
| | - Omotayo O Erejuwa
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Medicine, College of Medical Sciences, Alex Ekwueme Federal University, Ndufu-Alike, Ikwo, Ebonyi State, Nigeria
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25
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Luo A, Xie Z, Wang Y, Wang X, Li S, Yan J, Zhan G, Zhou Z, Zhao Y, Li S. Type 2 diabetes mellitus-associated cognitive dysfunction: Advances in potential mechanisms and therapies. Neurosci Biobehav Rev 2022; 137:104642. [PMID: 35367221 DOI: 10.1016/j.neubiorev.2022.104642] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2021] [Revised: 03/24/2022] [Accepted: 03/27/2022] [Indexed: 12/22/2022]
Abstract
Type 2 diabetes (T2D) and its target organ injuries cause distressing impacts on personal health and put an enormous burden on the healthcare system, and increasing attention has been paid to T2D-associated cognitive dysfunction (TDACD). TDACD is characterized by cognitive dysfunction, delayed executive ability, and impeded information-processing speed. Brain imaging data suggest that extensive brain regions are affected in patients with T2D. Based on current findings, a wide spectrum of non-specific neurodegenerative mechanisms that partially overlap with the mechanisms of neurodegenerative diseases is hypothesized to be associated with TDACD. However, it remains unclear whether TDACD is a consequence of T2D or a complication that co-occurs with T2D. Theoretically, anti-diabetes methods are promising neuromodulatory approaches to reduce brain injury in patients with T2D. In this review, we summarize potential mechanisms underlying TDACD and promising neurotropic effects of anti-diabetes methods and some neuroprotective natural compounds. Constructing screening or diagnostic tools and developing targeted treatment and preventive strategies would be expected to reduce the burden of TDACD.
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Affiliation(s)
- Ailin Luo
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Zheng Xie
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Yue Wang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Xuan Wang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Shan Li
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Jing Yan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Gaofeng Zhan
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Zhiqiang Zhou
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Yilin Zhao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
| | - Shiyong Li
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology.
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26
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Omarigliptin attenuates rotenone-induced Parkinson's disease in rats: Possible role of oxidative stress, endoplasmic reticulum stress and immune modulation. Food Chem Toxicol 2022; 164:113015. [PMID: 35439590 DOI: 10.1016/j.fct.2022.113015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 04/02/2022] [Accepted: 04/11/2022] [Indexed: 11/20/2022]
Abstract
The current study aimed to explore the potential neuroprotective effect of omarigliptin (OG), an antidiabetic drug that crosses the blood-brain barrier (BBB), in a Parkinson's disease (PD) rotenone-based rat-model. Results showed that OG attenuated motor impairment, histological aberrations, α-synuclein accumulation, and rescued the dopaminergic neurons in rotenone-administered rats. Furthermore, OG halted rotenone-induced oxidative stress; as shown by reduced lipid peroxidation, decline in the oxidative stress sensor (nuclear factor erythroid 2-related factor 2) and its downstream heme oxygenase-1. In addition, OG abrogated neuroinflammation and apoptosis in rotenone-treated rats. Moreover, OG ameliorated endoplasmic reticulum (ER) stress in rotenone-administered rats; as evidenced by reduced levels of ER resident proteins such as glucose-regulated protein 78, C/EBP homologous protein and apoptotic caspase-12. In conclusion, this study implies repurposing of OG, as a novel neuroprotective agent due to its antioxidant properties, its effects on ER stress in addition to its anti-inflammatory and anti-apoptotic activities.
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Khodir SA, Faried MA, Abd-Elhafiz HI, Sweed EM. Sitagliptin Attenuates the Cognitive Deficits in L-Methionine-Induced Vascular Dementia in Rats. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7222590. [PMID: 35265716 PMCID: PMC8898801 DOI: 10.1155/2022/7222590] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 01/29/2022] [Indexed: 02/05/2023]
Abstract
Vascular dementia (VaD) is the second most prevalent type of dementia characterized by progressive cognitive deficits and is a major risk factor for the development of Alzheimer's disease and other neurodegenerative disorders. This study is aimed at determining the potential neuroprotective effect of sitagliptin (STG) on cognitive deficits in L-methionine-induced VaD in rats and the possible underlying mechanisms. 30 adult male Wistar albino rats were divided equally (n = 10) into three groups: control, VaD, and VaD + STG groups. The cognitive performance of the animals was conducted by open field, elevated plus maze, Y-maze, novel object recognition, and Morris water maze tests. Serum homocysteine, TNF-α, IL-6, IL-10, total cholesterol, and triglycerides levels were assessed together with hippocampal MDA, SOD, and BDNF. Histopathological and immunohistochemical assessments of the thoracic aorta and hippocampus (CA1 region) were also performed. Chronic L-methionine administration impaired memory and learning and induced anxiety. On the other hand, STG protected against cognitive deficits through improving oxidative stress biomarkers, inflammatory mediators, lipid profiles, and hippocampus level of BDNF as well as decreasing caspase-3 and GFAP and increasing Ki-67 immunoreactions in the hippocampus. Also, STG improved the endothelial dysfunction via upregulation of aortic eNOS immunoreaction. STG improved the cognitive deficits of L-methionine-induced VaD by its antioxidant, anti-inflammatory, antiapoptotic, and neurotrophic effects. These findings suggest that STG may be a promising future agent for protection against VaD.
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Affiliation(s)
- Suzan A. Khodir
- Medical Physiology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Manar A. Faried
- Human Anatomy and Embryology, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Huda I. Abd-Elhafiz
- Clinical Pharmacology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Eman M. Sweed
- Clinical Pharmacology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
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Iwasa K, Yamamoto S, Yamashina K, Yagishita-Kyo N, Maruyama K, Awaji T, Takei Y, Hirasawa A, Yoshikawa K. A peripheral lipid sensor GPR120 remotely contributes to suppression of PGD 2-microglia-provoked neuroinflammation and neurodegeneration in the mouse hippocampus. J Neuroinflammation 2021; 18:304. [PMID: 34961526 PMCID: PMC8711188 DOI: 10.1186/s12974-021-02361-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 12/16/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Neuroinflammation is a key pathological component of neurodegenerative disease and is characterized by microglial activation and the secretion of proinflammatory mediators. We previously reported that a surge in prostaglandin D2 (PGD2) production and PGD2-induced microglial activation could provoke neuroinflammation. We also reported that a lipid sensor GPR120 (free fatty acid receptor 4), which is expressed in intestine, could be activated by polyunsaturated fatty acids (PUFA), thereby mediating secretion of glucagon-like peptide-1 (GLP-1). Dysfunction of GPR120 results in obesity in both mice and humans. METHODS To reveal the relationship between PGD2-microglia-provoked neuroinflammation and intestinal PUFA/GPR120 signaling, we investigated neuroinflammation and neuronal function with gene and protein expression, histological, and behavioral analysis in GPR120 knockout (KO) mice. RESULTS In the current study, we discovered notable neuroinflammation (increased PGD2 production and microglial activation) and neurodegeneration (declines in neurogenesis, hippocampal volume, and cognitive function) in GPR120 KO mice. We also found that Hematopoietic-prostaglandin D synthase (H-PGDS) was expressed in microglia, microglia were activated by PGD2, H-PGDS expression was upregulated in GPR120 KO hippocampus, and inhibition of PGD2 production attenuated this neuroinflammation. GPR120 KO mice exhibited reduced intestinal, plasma, and intracerebral GLP-1 contents. Peripheral administration of a GLP-1 analogue, liraglutide, reduced PGD2-microglia-provoked neuroinflammation and further neurodegeneration in GPR120 KO mice. CONCLUSIONS Our results suggest that neurological phenotypes in GPR120 KO mice are probably caused by dysfunction of intestinal GPR120. These observations raise the possibility that intestinal GLP-1 secretion, stimulated by intestinal GPR120, may remotely contributed to suppress PGD2-microglia-provoked neuroinflammation in the hippocampus.
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Affiliation(s)
- Kensuke Iwasa
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan
| | - Shinji Yamamoto
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan
| | - Kota Yamashina
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan
| | - Nan Yagishita-Kyo
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan
| | - Kei Maruyama
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan
| | - Takeo Awaji
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan
| | - Yoshinori Takei
- Department of Translational Research and Cellular Therapeutics, School of Medicine, Faculty of Medicine, Toho University, 5-21-16 Omori-Nishi, Ota-ku, Tokyo, 143-8540, Japan
| | - Akira Hirasawa
- Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.,Institute for Integrated Medical Sciences, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
| | - Keisuke Yoshikawa
- Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan.
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29
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Sana SRGL, Li EY, Deng XJ, Guo L. Association between plasma dipeptidyl peptidase-4 levels and cognitive function in perinatal pregnant women with gestational diabetes mellitus. World J Clin Cases 2021; 9:10161-10171. [PMID: 34904086 PMCID: PMC8638028 DOI: 10.12998/wjcc.v9.i33.10161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 07/13/2021] [Accepted: 09/06/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Dipeptidyl peptidase-4 (DPP4) is associated with cognitive dysfunction in patients with type 2 diabetes.
AIM To assess a possible relationship between serum DPP4 and cognitive function in perinatal pregnant women with gestational diabetes mellitus (GDM).
METHODS The study subjects were divided into three groups: GDM group (n = 81), healthy pregnant (HP) group (n = 85), and control group (n = 51). The Montreal Cognitive Assessment (MoCA) was used to assess the cognitive status of each group. Venous blood samples were collected to measure blood lipids, glycated hemoglobin, and glucose levels. For each participant, a 3-mL blood sample was collected and centrifuged, and the serum was collected. Blood samples were stored at -80 ℃, and DPP4, interleukin-6 (IL-6), and 8-iso-prostaglandin F2α (8-iso-PGF2α), and brain-derived neurotrophic factor (BDNF) were detected using ELISA.
RESULTS The MoCA scores in the GDM and HP groups were significantly different from those in the control group in terms of visuospatial/executive function and attention (P < 0.05); however, the scores were not significantly different between the GDM and HP groups (P > 0.05). In terms of language, the GDM group had significantly different scores from those in the other two groups (P < 0.05). In terms of memory, a significant difference was found between the HP and control groups (P < 0.05), as well as between the GDM and HP groups. The levels of DPP4, IL-6, and 8-iso-PGF2α in the GDM group were significantly higher than those in the HP and control groups (P < 0.05); however, the differences between these levels in the HP and control groups were not significant (P > 0.05). The level of BDNF in the GDM group was significantly lower than that in the HP and control groups (P < 0.05), although the difference in this level between the HP and control groups was not significant (P > 0.05).
CONCLUSION Cognitive dysfunction in perinatal pregnant women with GDM mainly manifested as memory loss, which might be associated with elevated DPP4 levels.
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Affiliation(s)
- Si-Ri-Gu-Leng Sana
- Department of Anesthesiology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - En-You Li
- Department of Anesthesiology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Xi-Jin Deng
- Department of Anesthesiology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Lei Guo
- Department of Anesthesiology, the First Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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Gao XR, Chen Z, Fang K, Xu JX, Ge JF. Protective effect of quercetin against the metabolic dysfunction of glucose and lipids and its associated learning and memory impairments in NAFLD rats. Lipids Health Dis 2021; 20:164. [PMID: 34789244 PMCID: PMC8596093 DOI: 10.1186/s12944-021-01590-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/28/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Quercetin (QUE) is a flavonol reported with anti-inflammatory and antioxidant activities, and previous results from the group of this study have demonstrated its neuroprotective effect against lipopolysaccharide-induced neuropsychiatric injuries. However, little is known about its potential effect on neuropsychiatric injuries induced or accompanied by metabolic dysfunction of glucose and lipids. METHODS A nonalcoholic fatty liver disease (NAFLD) rat model was induced via a high-fat diet (HFD), and glucolipid parameters and liver function were measured. Behavioral performance was observed via the open field test (OFT) and the Morris water maze (MWM). The plasma levels of triggering receptor expressed on myeloid cells-1 (TREM1) and TREM2 were measured via enzyme-linked immunosorbent assay (ELISA). The protein expression levels of Synapsin-1 (Syn-1), Synaptatogmin-1 (Syt-1), TREM1 and TREM2 in the hippocampus were detected using western blotting. Morphological changes in the liver and hippocampus were detected by HE and Oil red or silver staining. RESULTS Compared with the control rats, HFD-induced NAFLD model rats presented significant metabolic dysfunction, hepatocyte steatosis, and impaired learning and memory ability, as indicated by the increased plasma concentrations of total cholesterol (TC) and triglyceride (TG), the impaired glucose tolerance, the accumulated fat droplets and balloon-like changes in the liver, and the increased escaping latency but decreased duration in the target quadrant in the Morris water maze. All these changes were reversed in QUE-treated rats. Moreover, apart from improving the morphological injuries in the hippocampus, treatment with QUE could increase the decreased plasma concentration and hippocampal protein expression of TREM1 in NAFLD rats and increase the decreased expression of Syn-1 and Syt-1 in the hippocampus. CONCLUSIONS These results suggested the therapeutic potential of QUE against NAFLD-associated impairment of learning and memory, and the mechanism might involve regulating the metabolic dysfunction of glucose and lipids and balancing the protein expression of synaptic plasticity markers and TREM1/2 in the hippocampus.
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Affiliation(s)
- Xin-Ran Gao
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, People's Republic of China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, China
| | - Zheng Chen
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, People's Republic of China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, China
| | - Ke Fang
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, People's Republic of China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, China
| | - Jing-Xian Xu
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, People's Republic of China
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, China
| | - Jin-Fang Ge
- School of Pharmacy, Anhui Medical University, 81 Meishan Road, Hefei, 230032, People's Republic of China.
- The Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Medical University, Hefei, China.
- Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, China.
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Linagliptin Protects Human SH-SY5Y Neuroblastoma Cells against Amyloid-β Cytotoxicity via the Activation of Wnt1 and Suppression of IL-6 Release. IRANIAN BIOMEDICAL JOURNAL 2021; 25:343-8. [PMID: 34425652 PMCID: PMC8487681 DOI: 10.52547/ibj.25.5.343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Background Alzheimer’s disease is one of the neurodegenerative disorders typified by the aggregate of amyloid-β (Aβ) and phosphorylated tau protein. Oxidative stress and neuroinflammation, because of Aβ peptides, are strongly involved in the pathophysiology of Alzheimer’s disease (AD). Linagliptin shows neuroprotective properties against AD pathological processes through alleviation of neural inflammation and AMPK activation. Methods We assessed the benefits of linagliptin pretreatment (at 10, 20, and 50 nM concentrations), against Aβ1-42 toxicity (20 μM) in SH-SY5Y cells. The concentrations of secreted cytokines, such as TNF-α, IL-6, and IL-1β, and signaling proteins, including pCREB, Wnt1, and PKCε, were quantified by ELISA. Results We observed that Aβ led to cellular inflammation, which was assessed by measuring inflammatory cytokines (TNF-α, IL-1β, and IL-6). Moreover, Aβ1-42 treatment impaired pCREB, PKCε, and Wnt1 signaling in human SH-SY5Y neuroblastoma cells. Addition of Linagliptin significantly reduced IL-6 levels in the lysates of cells, treated with Aβ1-42. Furthermore, linagliptin prevented the downregulation of Wnt1 in Aβ1-42-treated cells exposed. Conclusion The current findings reveal that linagliptin alleviates Aβ1-42-induced inflammation in SH-SY5Y cells, probably through the suppression of IL-6 release, and some of its benefits are mediated through the activation of the Wnt1 signaling pathway.
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Jeong SH, Kim HR, Kim J, Kim H, Hong N, Jung JH, Baik K, Cho H, Lyoo CH, Ye BS, Sohn YH, Seong JK, Lee PH. Association of Dipeptidyl Peptidase-4 Inhibitor Use and Amyloid Burden in Diabetic Patients With AD-Related Cognitive Impairment. Neurology 2021; 97:e1110-e1122. [PMID: 34380754 DOI: 10.1212/wnl.0000000000012534] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 07/09/2021] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVES To investigate whether dipeptidyl peptidase-4 inhibitors (DPP-4i) have beneficial effects on amyloid aggregation and longitudinal cognitive outcome in diabetic Alzheimer's disease-related cognitive impairment (ADCI). METHODS We retrospectively reviewed 282 patients with ADCI who had positive scan of 18F-florbetaben amyloid PET images were classified into three groups according to a prior diagnosis of diabetes and DPP-4i use: diabetic patients being treated with (ADCI-DPP-4i+, n=70) or without DPP-4i (ADCI-DPP-4i-, n=71), and non-diabetic patients (n=141). Multiple linear regression analyses were performed to determine inter-group differences in global and regional amyloid retention using standardized uptake value ratios calculated from cortical areas. We assessed the longitudinal changes in Mini-Mental State Examination (MMSE) score using a linear mixed model. RESULTS The ADCI-DPP-4i+ group had lower global amyloid burden than the ADCI-DPP-4i- group (β = 0.075, SE = 0.024, p = 0.002) and the non-diabetic ADCI group (β = 0.054, SE = 0.021, p = 0.010) after adjusting for age, sex, education, cognitive status, and APOE ε4 carrier status. Additionally, the ADCI-DPP-4i+ group had lower regional amyloid burden in temporo-parietal areas than either the ADCI-DPP-4i- group or the non-diabetic ADCI group. The ADCI-DPP-4i+ group showed a slower longitudinal decrease in MMSE score (β = 0.772, SE = 0.272, p = 0.005) and memory recall sub-score (β = 0.291, SE = 0.116, p = 0.012) than the ADCI-DPP-4i- group. CONCLUSIONS These findings suggest that DPP-4i use is associated with low amyloid burden and favorable long-term cognitive outcome in diabetic patients with ADCI.
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Affiliation(s)
- Seong Ho Jeong
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.,Sanggye Paik Hospital, Inje University College of Medicine, Seoul, South Korea
| | - Hye Ryun Kim
- Global Health Technology Research Center, College of Health Science, Korea University, Seoul, South Korea
| | - Jeonghun Kim
- Medical & Health Device Division, Korea Testing Laboratory, Seoul, South Korea
| | - Hankyeol Kim
- Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Namki Hong
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Jin Ho Jung
- Department of Neurology, Busan Paik Hospital, Inje University College of Medicine, Busan, South Korea
| | - Kyoungwon Baik
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hanna Cho
- Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Chul Hyoung Lyoo
- Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Byoung Seok Ye
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Young H Sohn
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Joon-Kyung Seong
- School of Biomedical Engineering, Korea University, Seoul, South Korea.,Department of Artificial Intelligence, Korea University, Seoul, South Korea
| | - Phil Hyu Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea .,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
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Chen Q, Cao T, Li N, Zeng C, Zhang S, Wu X, Zhang B, Cai H. Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders. Front Pharmacol 2021; 12:667874. [PMID: 34108878 PMCID: PMC8182376 DOI: 10.3389/fphar.2021.667874] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 05/07/2021] [Indexed: 12/16/2022] Open
Abstract
Cognitive impairment is a shared abnormality between type 2 diabetes mellitus (T2DM) and many neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and schizophrenia. Emerging evidence suggests that brain insulin resistance plays a significant role in cognitive deficits, which provides the possibility of anti-diabetic agents repositioning to alleviate cognitive deficits. Both preclinical and clinical studies have evaluated the potential cognitive enhancement effects of anti-diabetic agents targeting the insulin pathway. Repurposing of anti-diabetic agents is considered to be promising for cognitive deficits prevention or control in these neurodegenerative and neuropsychiatric disorders. This article reviewed the possible relationship between brain insulin resistance and cognitive deficits. In addition, promising therapeutic interventions, especially current advances in anti-diabetic agents targeting the insulin pathway to alleviate cognitive impairment in AD and schizophrenia were also summarized.
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Affiliation(s)
- Qian Chen
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Ting Cao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - NaNa Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Cuirong Zeng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Shuangyang Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Xiangxin Wu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Hualin Cai
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
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Lafferty RA, O’Harte FPM, Irwin N, Gault VA, Flatt PR. Proglucagon-Derived Peptides as Therapeutics. Front Endocrinol (Lausanne) 2021; 12:689678. [PMID: 34093449 PMCID: PMC8171296 DOI: 10.3389/fendo.2021.689678] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 05/05/2021] [Indexed: 12/12/2022] Open
Abstract
Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.
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Affiliation(s)
| | | | | | - Victor A. Gault
- School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom
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35
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Jeong SH, Chung SJ, Yoo HS, Hong N, Jung JH, Baik K, Lee YH, Sohn YH, Lee PH. Beneficial effects of dipeptidyl peptidase-4 inhibitors in diabetic Parkinson's disease. Brain 2021; 144:1127-1137. [PMID: 33895825 DOI: 10.1093/brain/awab015] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/10/2020] [Accepted: 11/10/2020] [Indexed: 12/11/2022] Open
Abstract
Dipeptidyl peptidase 4 (DPP4) inhibitors are widely used hypoglycaemic agents and improve glucose metabolism by enhancing the bioavailability of active glucagon-like peptide-1. In this study, we hypothesized that treatment with DPP4 inhibitors may have beneficial effects on nigrostriatal dopamine and longitudinal motor performance in diabetic patients with Parkinson's disease. We classified 697 drug naive patients with de novo Parkinson's disease who had undergone dopamine transporter imaging into three groups according to a prior diagnosis of diabetes and use of DPP4 inhibitors: diabetic patients with Parkinson's disease being treated with (n = 54) or without DPP4 inhibitors (n = 85), and non-diabetic patients with Parkinson's disease (n = 558). Diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had a higher baseline dopamine transporter availability in the anterior (2.56 ± 0.74 versus 2.10 ± 0.50; P = 0.016), posterior (1.83 ± 0.69 versus 1.40 ± 0.50; P < 0.001), and ventral putamina (1.72 ± 0.58 versus 1.35 ± 0.37; P = 0.001) than that in diabetic patients with Parkinson's disease without DPP4 inhibitors. Additionally, diabetic patients with Parkinson's disease being treated with DPP4 inhibitors had higher dopamine transporter availability in the posterior putamen than that in non-diabetic patients with Parkinson's disease (1.83 ± 0.69 versus 1.43 ± 0.59; P < 0.001). After adjusting for age, sex, disease duration, and vascular risk factors, linear regression models showed that a prior treatment of DPP4 inhibitors remained independently and significantly associated with dopamine transporter availability in the anterior (β = -0.186, P = 0.012; β = -0.207, P = 0.003), posterior (β = -0.336, P < 0.001; β = -0.286, P < 0.001), and ventral putamina (β = -0.204, P = 0.005; β = -0.250, P < 0.001). A linear mixed model revealed that the diabetic group with Parkinson's disease being treated with DPP4 inhibitors had a slower longitudinal increase in levodopa-equivalent dose than the other groups (P = 0.003). Survival analyses showed that the rate of levodopa-induced dyskinesia was significantly lower in the diabetic group with a prior treatment with DPP4 inhibitors than the diabetic group without DPP4 inhibitors (hazard ratio = 0.194, P = 0.037). These findings suggest that DPP4 inhibitors may confer beneficial effects on the baseline nigrostriatal dopamine degeneration and long-term motor outcomes in diabetic patients with Parkinson's disease and may extend its role into non-diabetic patients with Parkinson's disease.
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Affiliation(s)
- Seong Ho Jeong
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Seok Jong Chung
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.,Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin, South Korea
| | - Han Soo Yoo
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Namki Hong
- Department of Internal Medicine, Severance Hospital, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, South Korea
| | - Jin Ho Jung
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Kyoungwon Baik
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Yang Hyun Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Young H Sohn
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea
| | - Phil Hyu Lee
- Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
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Coulter-Parkhill A, McClean S, Gault VA, Irwin N. Therapeutic Potential of Peptides Derived from Animal Venoms: Current Views and Emerging Drugs for Diabetes. Clin Med Insights Endocrinol Diabetes 2021; 14:11795514211006071. [PMID: 34621137 PMCID: PMC8491154 DOI: 10.1177/11795514211006071] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/10/2021] [Indexed: 12/13/2022] Open
Abstract
The therapeutic potential of venom-derived drugs is evident today. Currently, several significant drugs are FDA approved for human use that descend directly from animal venom products, with others having undergone, or progressing through, clinical trials. In addition, there is growing awareness of the important cosmeceutical application of venom-derived products. The success of venom-derived compounds is linked to their increased bioactivity, specificity and stability when compared to synthetically engineered compounds. This review highlights advancements in venom-derived compounds for the treatment of diabetes and related disorders. Exendin-4, originating from the saliva of Gila monster lizard, represents proof-of-concept for this drug discovery pathway in diabetes. More recent evidence emphasises the potential of venom-derived compounds from bees, cone snails, sea anemones, scorpions, snakes and spiders to effectively manage glycaemic control. Such compounds could represent exciting exploitable scaffolds for future drug discovery in diabetes, as well as providing tools to allow for a better understanding of cell signalling pathways linked to insulin secretion and metabolism.
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Affiliation(s)
| | | | - Victor A Gault
- Diabetes Research Group, Ulster University, Coleraine, UK
| | - Nigel Irwin
- Diabetes Research Group, Ulster University, Coleraine, UK
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37
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Tyagi A, Pugazhenthi S. Targeting Insulin Resistance to Treat Cognitive Dysfunction. Mol Neurobiol 2021; 58:2672-2691. [PMID: 33483903 DOI: 10.1007/s12035-021-02283-3] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023]
Abstract
Dementia is a devastating disease associated with aging. Alzheimer's disease is the most common form of dementia, followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus, characterized by chronic hyperglycemia and insulin resistance, as a risk factor for Alzheimer's disease and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported by recent clinical and preclinical studies. The findings from these studies suggest that antidiabetic drugs have the potential to be used to treat dementia. In this review, we discuss the physiological functions of insulin in the brain, studies on the evaluation of cognitive function under conditions of insulin resistance, and reports on the beneficial actions of antidiabetic drugs in the brain. This review covers clinical studies as well as investigations in animal models and will further highlight the emerging link between insulin resistance and neurodegenerative disorders.
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Affiliation(s)
- Anit Tyagi
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.,Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.,University of Denver, Denver, CO, USA
| | - Subbiah Pugazhenthi
- Rocky Mountain Regional VA Medical Center, Aurora, CO, USA. .,Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora, CO, USA.
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The methionine aminopeptidase 2 inhibitor, TNP-470, enhances the antidiabetic properties of sitagliptin in mice by upregulating xenin. Biochem Pharmacol 2020; 183:114355. [PMID: 33279496 DOI: 10.1016/j.bcp.2020.114355] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/12/2020] [Accepted: 12/01/2020] [Indexed: 12/24/2022]
Abstract
The therapeutic mechanism of action of methionine aminopeptidase 2 (MetAP2) inhibitors for obesity-diabetes has not yet been fully defined. Xenin, a K-cell derived peptide hormone, possesses an N-terminal Met amino acid residue. Thus, elevated xenin levels could represent a potential pharmacological mechanism of MetAP2 inhibitors, since long-acting xenin analogues have been shown to improve obesity-diabetes. The present study has assessed the ability of the MetAP2 inhibitor, TNP-470, to augment the antidiabetic utility of the incretin-enhancer drug, sitagliptin, in high fat fed (HFF) mice. TNP-470 (1 mg/kg) and sitagliptin (25 mg/kg) were administered once-daily alone, or in combination, to diabetic HFF mice (n = 10) for 18 days. Individual therapy with TNP-470 or sitagliptin resulted in numerous metabolic benefits including reduced blood glucose, increased circulating and pancreatic insulin and improved glucose tolerance, insulin sensitivity, pyruvate tolerance and overall pancreatic islet architecture. Further assessment of metabolic rate revealed that all treatments reduced respiratory exchange ratio and increased locomotor activity. All sitagliptin treated mice also exhibited increased energy expenditure. In addition, treatment with TNP-470 alone, or in combination with sitagliptin, reduced food intake and body weight, as well as elevating plasma and intestinal xenin. Importantly, combined sitagliptin and TNP-470 therapy was associated with further significant benefits beyond that observed by either treatment alone. This included more rapid restoration of normoglycaemia, superior glucose tolerance, increased circulating GIP concentrations and an enhanced pancreatic beta:alpha cell ratio. In conclusion, these data demonstrate that TNP-470 increases plasma and intestinal xenin levels, and augments the antidiabetic advantages of sitagliptin.
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Lee H, Kim E. Repositioning medication for cardiovascular and cerebrovascular disease to delay the onset and prevent progression of Alzheimer's disease. Arch Pharm Res 2020; 43:932-960. [PMID: 32909178 DOI: 10.1007/s12272-020-01268-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 08/31/2020] [Indexed: 02/08/2023]
Abstract
Alzheimer's disease (AD) is a complex, progressive, neurodegenerative disorder. As with other common chronic diseases, multiple risk factors contribute to the onset and progression of AD. Many researchers have evaluated the epidemiologic and pathophysiological association between AD, cardiovascular diseases (CVDs), and cerebrovascular diseases (CBVDs), including commonly reported risk factors such as diabetes, hypertension, and dyslipidemia. Relevant therapies of CVDs/CBVDs for the attenuation of AD have also been empirically investigated. Considering the challenges of new drug development, in terms of cost and time, multifactorial approaches such as therapeutic repositioning of CVD/CBVD medication should be explored to delay the onset and progression of AD. Thus, in this review, we discuss our current understanding of the association between cardiovascular risk factors and AD, as revealed by clinical and non-clinical studies, as well as the therapeutic implications of CVD/CBVD medication that may attenuate AD. Furthermore, we discuss future directions by evaluating ongoing trials in the field.
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Affiliation(s)
- Heeyoung Lee
- Department of Clinical Medicinal Sciences, Konyang University, 121 Daehakro, Nonsan, 32992, Republic of Korea
| | - EunYoung Kim
- Evidence-Based Research Laboratory, Division of Clinical Pharmacotherapy, College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea.
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Kim YK, Kim OY, Song J. Alleviation of Depression by Glucagon-Like Peptide 1 Through the Regulation of Neuroinflammation, Neurotransmitters, Neurogenesis, and Synaptic Function. Front Pharmacol 2020; 11:1270. [PMID: 32922295 PMCID: PMC7456867 DOI: 10.3389/fphar.2020.01270] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/31/2020] [Indexed: 12/11/2022] Open
Abstract
Depression has emerged as a major cause of mortality globally. Many studies have reported risk factors and mechanisms associated with depression, but it is as yet unclear how these findings can be applied to the treatment and prevention of this disorder. The onset and recurrence of depression have been linked to diverse metabolic factors, including hyperglycemia, dyslipidemia, and insulin resistance. Recent studies have suggested that depression is accompanied by memory loss as well as depressive mood. Thus, many researchers have highlighted the relationship between depressive behavior and metabolic alterations from various perspectives. Glucagon-like peptide-1 (GLP-1), which is secreted from gut cells and hindbrain areas, has been studied in metabolic diseases such as obesity and diabetes, and was shown to control glucose metabolism and insulin resistance. Recently, GLP-1 was highlighted as a regulator of diverse pathways, but its potential as the therapeutic target of depressive disorder was not described comprehensively. Therefore, in this review, we focused on the potential of GLP-1 modulation in depression.
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Affiliation(s)
- Young-Kook Kim
- Department of Biochemistry, Chonnam National University Medical School, Hwasun, South Korea
| | - Oh Yoen Kim
- Department of Food Science and Nutrition, Dong-A University, Busan, South Korea.,Center for Silver-targeted Biomaterials, Brain Busan 21 Plus Program, Graduate School, Dong-A University, Busan, South Korea
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun, South Korea
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41
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Liu S, Wang X, Deng H, Xia Y, Yang X, Chen Q. Effect of dipeptidyl peptidase-4 inhibitors inhibitor on cognitive dysfunction in diabetes: A protocol for systematic review and meta analysis. Medicine (Baltimore) 2020; 99:e20707. [PMID: 32756077 PMCID: PMC7402785 DOI: 10.1097/md.0000000000020707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 05/15/2020] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION There is a risk of cognitive impairment in diabetic patients. Some studies have shown that dipeptidyl peptidase-4 inhibitors (DPP-4) inhibitors can play a protective role in controlling blood glucose and blocking the DPP-4 to attach antibody glucagon-like peptide -1 degradation and prolong antibody glucagon-like peptide -1, promoting the growth of neurites and the formation of synapses. The purpose of this study is to explore the effect of the DPP-4 inhibitor on cognitive impairment in diabetic patients by meta-analysis. METHODS The system review plan will strictly follow the Systematic Review and Meta-Analysis Protocols entry for reporting. PubMed, EMBASE, Cochrane Library, Clinicaltrials(clinicaltrials.gov), Web of Science, China National Knowledge Infrastructure, China Science and Technology Journal Database and Wanfang Databases will be systematically searched, and all randomized controlled trials comparing DPP-4 inhibitors with placebo or other hypoglycemic drugs to study cognitive impairment in type 2 diabetic patients will be included. The inclusion, evaluation and data extraction of the literature will be conducted by 2 persons independently, and the dispute will be resolved by a third person. All the meta-analysis of the included literature and the research progress of the existing research are analyzed as the main results. ETHICS AND DISSEMINATION It is to evaluate and analyze the completed research, so there is no ethical problem. The research results will be published in a peer-reviewed journal. REGISTRATION The protocol of this systematic review and meta-analysis was registered on International Platform of Registered Systematic Review and Meta-analysis Protocols (https://inplasy.com/) (number. 202040185).
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Affiliation(s)
| | | | | | | | | | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Safar MM, Shahin NN, Mohamed AF, Abdelkader NF. Suppression of BACE1 and amyloidogenic/RAGE axis by sitagliptin ameliorates PTZ kindling-induced cognitive deficits in rats. Chem Biol Interact 2020; 328:109144. [PMID: 32653415 DOI: 10.1016/j.cbi.2020.109144] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 05/22/2020] [Accepted: 05/27/2020] [Indexed: 12/22/2022]
Abstract
The debilitating nature of cognitive impairment in epilepsy and the potential of some traditional antiepileptics to further deteriorate cognitive function are areas of growing concern. Glucagon-like peptide-1 (GLP-1) deficiency has been linked to reduced seizure threshold as well as cognitive dysfunction. Here, we tested whether sitagliptin (SITA), by virtue of its neuroprotective properties, could alleviate both epilepsy and associated cognitive dysfunction in a rat model of kindling epilepsy. Chemical kindling was induced by subconvulsive doses of pentylenetetrazol (PTZ) (30 mg/kg; i.p). SITA (50 mg/kg; p.o) was administered 1 h before PTZ injections. SITA conceivably attenuated PTZ hippocampal histological insult, preserved neuronal integrity and amended neurotransmitter perturbations in rat hippocampi paralleled with enhanced hippocampal GLP-1 levels as well as the downstream cAMP content and protein kinase A (PKA) activity. Moreover, SITA improved cognitive functioning of rats in the Morris water maze which was coupled with hampered hippocampal p(Ser404)-tau and β-amyloid proteins. SITA replenished p(Ser9)-glycogen synthase kinase-3β (GSK-3β). It also opposed the boosted matrix metalloproteinase-9 (MMP-9), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF-1) levels associated with PTZ administration along with mitigation of both β-secretase-1 (BACE1) immunoreactivity and receptor for advanced glycation end products (RAGE) protein level in rat hippocampi. In conclusion, SITA subdues epileptic and cognitive upshots of PTZ kindling in rats, which might correspond to the modulation of BACE1, amyloidogenic/RAGE axis as well as GSK-3β/MMP-9/BDNF signaling cascade. SITA effects are probably mediated via boosting GLP-1 and subsequently enhancing GLP-1/GLP-1R signaling.
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Affiliation(s)
- Marwa M Safar
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt; Pharmacology and Biochemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt
| | - Nancy N Shahin
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Ahmed F Mohamed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Noha F Abdelkader
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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43
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Pleiotropic effects of anti-diabetic drugs: A comprehensive review. Eur J Pharmacol 2020; 884:173349. [PMID: 32650008 DOI: 10.1016/j.ejphar.2020.173349] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 06/24/2020] [Accepted: 07/03/2020] [Indexed: 12/18/2022]
Abstract
Diabetes mellitus characterized by hyperglycaemia presents an array of comorbidities such as cardiovascular and renal failure, dyslipidemia, and cognitive impairments. Populations above the age of 60 are in an urgent need of effective therapies to deal with the complications associated with diabetes mellitus. Widely used anti-diabetic drugs have good safety profiles and multiple reports indicate their pleiotropic effects in diabetic patients or models. This review has been written with the objective of identifying the widely-marketed anti-diabetic drugs which can be efficiently repurposed for the treatment of other diseases or disorders. It is an updated, comprehensive review, describing the protective role of various classes of anti-diabetic drugs in mitigating the macro and micro vascular complications of diabetes mellitus, and differentiating these drugs on the basis of their mode of action. Notably, metformin, the anti-diabetic drug most commonly explored for cancer therapy, has also exhibited some antimicrobial effects. Unlike class specific effects, few instances of drug specific effects in managing cardiovascular complications have also been reported. A major drawback is that the pleiotropic effects of anti-diabetic drugs have been mostly investigated only in diabetic patients. Thus, for effective repurposing, more clinical trials devoted to analyse the effects of anti-diabetic drugs in patients irrespective of their diabetic condition, are required.
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Han W, Li Y, Cheng J, Zhang J, Chen D, Fang M, Xiang G, Wu Y, Zhang H, Xu K, Wang H, Xie L, Xiao J. Sitagliptin improves functional recovery via GLP-1R-induced anti-apoptosis and facilitation of axonal regeneration after spinal cord injury. J Cell Mol Med 2020; 24:8687-8702. [PMID: 32573108 PMCID: PMC7412681 DOI: 10.1111/jcmm.15501] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 05/18/2020] [Accepted: 05/28/2020] [Indexed: 12/18/2022] Open
Abstract
Axon growth and neuronal apoptosis are considered to be crucial therapeutic targets against spinal cord injury (SCI). Growing evidences have reported stimulation of glucagon‐like peptide‐1 (GLP‐1)/GLP‐1 receptor (GLP‐1R) signalling axis provides neuroprotection in experimental models of neurodegeneration disease. Endogenous GLP‐1 is rapidly degraded by dipeptidyl peptidase‐IV (DPP4), resulting in blocking of GLP‐1/GLP1R signalling process. Sitagliptin, a highly selective inhibitor of DPP4, has approved to have beneficial effects on diseases in which neurons damaged. However, the roles and the underlying mechanisms of sitagliptin in SCI repairing remain unclear. In this study, we used a rat model of SCI and PC12 cells/primary cortical neurons to explore the mechanism of sitagliptin underlying SCI recovery. We discovered the expression of GLP‐1R decreased in the SCI model. Administration of sitagliptin significantly increased GLP‐1R protein level, alleviated neuronal apoptosis, enhanced axon regeneration and improved functional recovery following SCI. Nevertheless, treatment with exendin9‐39, a GLP‐1R inhibitor, remarkably reversed the protective effect of sitagliptin. Additionally, we detected the AMPK/PGC‐1α signalling pathway was activated by sitagliptin stimulating GLP‐1R. Taken together, sitagliptin may be a potential agent for axon regrowth and locomotor functional repair via GLP‐1R‐induced AMPK/ PGC‐1α signalling pathway after SCI.
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Affiliation(s)
- Wen Han
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Yao Li
- Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiangting Cheng
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Jing Zhang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Dingwen Chen
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Mingqiao Fang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.,Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Guangheng Xiang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.,Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yanqing Wu
- Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Hongyu Zhang
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Ke Xu
- Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, The Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Hangxiang Wang
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Ling Xie
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
| | - Jian Xiao
- Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China
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Can dipeptidyl peptidase-4 inhibitors treat cognitive disorders? Pharmacol Ther 2020; 212:107559. [PMID: 32380197 DOI: 10.1016/j.pharmthera.2020.107559] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 04/24/2020] [Accepted: 04/29/2020] [Indexed: 12/13/2022]
Abstract
The linkage of neurodegenerative diseases with insulin resistance (IR) and type 2 diabetes mellitus (T2DM), including oxidative stress, mitochondrial dysfunction, excessive inflammatory responses and abnormal protein processing, and the correlation between cerebrovascular diseases and hyperglycemia has opened a new window for novel therapeutics for these cognitive disorders. Various antidiabetic agents have been studied for their potential treatment of cognitive disorders, among which the dipeptidyl peptidase-4 (DPP-4) inhibitors have been investigated more recently. So far, DPP-4 inhibitors have demonstrated neuroprotection and cognitive improvements in animal models, and cognitive benefits in diabetic patients with or without cognitive impairments. This review aims to summarize the potential mechanisms, advantages and limitations, and currently available evidence for developing DPP-4 inhibitors as a treatment of cognitive disorders.
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46
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Apigenin modulates hippocampal CREB-BDNF signaling in high fat, high fructose diet-fed rats. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.103898] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Ates Bulut E, Sahin Alak ZY, Dokuzlar O, Kocyigit SE, Soysal P, Smith L, Isik AT. Cognitive and metabolic outcomes of vildagliptin addition to the therapy in patients with type 2 diabetes mellitus: 26 week follow-up study. Arch Gerontol Geriatr 2020; 88:104013. [DOI: 10.1016/j.archger.2020.104013] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/30/2019] [Accepted: 01/17/2020] [Indexed: 01/28/2023]
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48
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Evaluation of sea cucumber peptides-assisted memory activity and acetylation modification in hippocampus of test mice based on scopolamine-induced experimental animal model of memory disorder. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.103909] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
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49
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Hung YW, Wang Y, Lee SL. DPP-4 inhibitor reduces striatal microglial deramification after sensorimotor cortex injury induced by external force impact. FASEB J 2020; 34:6950-6964. [PMID: 32246809 DOI: 10.1096/fj.201902818r] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 03/08/2020] [Accepted: 03/17/2020] [Indexed: 12/12/2022]
Abstract
Dipeptidyl peptidase-4 inhibitors (or gliptins), a class of antidiabetic drugs, have recently been shown to have protective actions in the central nervous system. Their cellular and molecular mechanisms responsible for these effects are largely unknown. In the present study, two structurally different gliptins, sitagliptin and vildagliptin, were examined for their therapeutic actions in a controlled cortical impact (CCI) model of moderate traumatic brain injury (TBI) in mice. Early post-CCI treatment with sitagliptin, but not vildagliptin, significantly reduced body asymmetry, locomotor hyperactivity, and brain lesion volume. Sitagliptin attenuated post-CCI microglial deramification in the ipsilateral dorsolateral (DL) striatum, while vildagliptin had no effect. Sitagliptin also reduced striatal expression of galectin-3 and monocyte chemoattractant protein 1(MCP-1), and increased the cortical and striatal levels of the anti-inflammatory cytokine IL-10 on the ipsilateral side. These data support a differential protective effect of sitagliptin against TBI, possibly mediated by an anti-inflammatory effect in striatum to preserve connective network. Both sitagliptin and vildagliptin produced similar increases of active glucagon-like peptide-1 (GLP-1) in blood and brain. Increasing active GLP-1 may not be the sole molecular mechanisms for the neurotherapeutic effect of sitagliptin in TBI.
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Affiliation(s)
- Yu-Wen Hung
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, R.O.C
| | - Yun Wang
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, R.O.C
| | - Sheau-Ling Lee
- Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan Town, Miaoli County, Taiwan, R.O.C
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50
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O'Harte FPM, Parthsarathy V, Flatt PR. Chronic apelin analogue administration is more effective than established incretin therapies for alleviating metabolic dysfunction in diabetic db/db mice. Mol Cell Endocrinol 2020; 504:110695. [PMID: 31904406 DOI: 10.1016/j.mce.2019.110695] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 11/26/2019] [Accepted: 12/27/2019] [Indexed: 01/24/2023]
Abstract
Stable apelin-13 peptide analogues have shown promising acute antidiabetic effects in mice with diet-induced obesity diabetes. Here the efficacy of (pGlu)apelin-13 amide (apelin amide) and the acylated analogue (pGlu)(Lys8GluPAL)apelin-13 amide (apelin FA), were examined following chronic administration in db/db mice, a genetic model of degenerative diabetes. Groups of 9-week old male db/db mice (n = 8) received twice daily injections (09:00 and 17:00 h; i.p.) or saline vehicle, apelin amide, apelin FA, or the established incretin therapies, exendin-4(1-39) or liraglutide, all at 25 nmol/kg body weight for 21 days. Control C57BL/6J mice were given saline twice daily. No changes in body weight or food intake were observed with either apelin or liraglutide treatments, but exendin-4 showed a reduction in cumulative food intake (p < 0.01) compared with saline-treated db/db mice. Apelin analogues and incretin mimetics induced sustained improvements of glycaemia (p < 0.05 to p < 0.001, from day 9-21), lowered HbA1c at 21 days (p < 0.05) and raised plasma insulin concentrations. The treatments also improved OGTT and ipGTT with enhanced insulin responses compared with saline-treated control db/db mice (p < 0.05 to p < 0.001). Apelin amide was superior to incretin mimetics in lowering plasma triglycerides by 34% (p < 0.05). Apelin analogues unlike both incretin mimetics reduced pancreatic α-cell area (p < 0.05 to p < 0.01) and all peptide treatments enhanced pancreatic insulin content (p < 0.05 to p < 0.01). In conclusion, longer-term administration of apelin-13 analogues, induced similar and in some respects more effective metabolic improvements than incretin mimetics in db/db mice, providing a viable alternative approach for counteracting metabolic dysfunction for mild and more degenerative forms of the disease.
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Affiliation(s)
- Finbarr P M O'Harte
- The SAAD Centre for Pharmacy & Diabetes, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
| | - Vadivel Parthsarathy
- The SAAD Centre for Pharmacy & Diabetes, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
| | - Peter R Flatt
- The SAAD Centre for Pharmacy & Diabetes, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK
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