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Escobar I, Xu J, Jackson CW, Stegelmann SD, Fagerli EA, Dave KR, Perez-Pinzon MA. Resveratrol Preconditioning Protects Against Ischemia-Induced Synaptic Dysfunction and Cofilin Hyperactivation in the Mouse Hippocampal Slice. Neurotherapeutics 2023; 20:1177-1197. [PMID: 37208551 PMCID: PMC10457274 DOI: 10.1007/s13311-023-01386-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2023] [Indexed: 05/21/2023] Open
Abstract
Perturbations in synaptic function are major determinants of several neurological diseases and have been associated with cognitive impairments after cerebral ischemia (CI). Although the mechanisms underlying CI-induced synaptic dysfunction have not been well defined, evidence suggests that early hyperactivation of the actin-binding protein, cofilin, plays a role. Given that synaptic impairments manifest shortly after CI, prophylactic strategies may offer a better approach to prevent/mitigate synaptic damage following an ischemic event. Our laboratory has previously demonstrated that resveratrol preconditioning (RPC) promotes cerebral ischemic tolerance, with many groups highlighting beneficial effects of resveratrol treatment on synaptic and cognitive function in other neurological conditions. Herein, we hypothesized that RPC would mitigate hippocampal synaptic dysfunction and pathological cofilin hyperactivation in an ex vivo model of ischemia. Various electrophysiological parameters and synaptic-related protein expression changes were measured under normal and ischemic conditions utilizing acute hippocampal slices derived from adult male mice treated with resveratrol (10 mg/kg) or vehicle 48 h prior. Remarkably, RPC significantly increased the latency to anoxic depolarization, decreased cytosolic calcium accumulation, prevented aberrant increases in synaptic transmission, and rescued deficits in long-term potentiation following ischemia. Additionally, RPC upregulated the expression of the activity-regulated cytoskeleton associated protein, Arc, which was partially required for RPC-mediated attenuation of cofilin hyperactivation. Taken together, these findings support a role for RPC in mitigating CI-induced excitotoxicity, synaptic dysfunction, and pathological over-activation of cofilin. Our study provides further insight into mechanisms underlying RPC-mediated neuroprotection against CI and implicates RPC as a promising strategy to preserve synaptic function after ischemia.
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Affiliation(s)
- Iris Escobar
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Department of Neurology, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Neuroscience Program, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
| | - Jing Xu
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Department of Neurology, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Neuroscience Program, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
| | - Charles W Jackson
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Department of Neurology, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Neuroscience Program, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
| | - Samuel D Stegelmann
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Department of Neurology, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
| | - Eric A Fagerli
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Department of Neurology, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Neuroscience Program, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
| | - Kunjan R Dave
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Department of Neurology, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
- Neuroscience Program, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA
| | - Miguel A Perez-Pinzon
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA.
- Department of Neurology, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA.
- Neuroscience Program, University of Miami Leonard M. Miller School of Medicine, PO Box 016960, Miami, FL, 33101, USA.
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Premarin Reduces Neurodegeneration and Promotes Improvement of Function in an Animal Model of Spinal Cord Injury. Int J Mol Sci 2022; 23:ijms23042384. [PMID: 35216504 PMCID: PMC8875481 DOI: 10.3390/ijms23042384] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/16/2022] [Accepted: 02/16/2022] [Indexed: 01/27/2023] Open
Abstract
Spinal cord injury (SCI) causes significant mortality and morbidity. Currently, no FDA-approved pharmacotherapy is available for treating SCI. Previously, low doses of estrogen (17β-estradiol, E2) were shown to improve the post-injury outcome in a rat SCI model. However, the range of associated side effects makes advocating its therapeutic use difficult. Therefore, this study aimed at investigating the therapeutic efficacy of Premarin (PRM) in SCI. PRM is an FDA-approved E2 (10%) formulation, which is used for hormone replacement therapy with minimal risk of serious side effects. The effects of PRM on SCI were examined by magnetic resonance imaging, immunofluorescent staining, and western blot analysis in a rat model. SCI animals treated with vehicle alone, PRM, E2 receptor antagonist (ICI), or PRM + ICI were graded in a blinded way for locomotor function by using the Basso–Beattie–Bresnahan (BBB) locomotor scale. PRM treatment for 7 days decreased post-SCI lesion volume and attenuated neuronal cell death, inflammation, and axonal damage. PRM also altered the balance of pro- and anti-apoptotic proteins in favor of cell survival and improved angiogenesis and microvascular growth. Increased expression of estrogen receptors (ERs) ERα and ERβ following PRM treatment and their inhibition by ER inhibitor indicated that the neuroprotection associated with PRM treatment might be E2-receptor mediated. The attenuation of glial activation with decreased inflammation and cell death, and increased angiogenesis by PRM led to improved functional outcome as determined by the BBB locomotor scale. These results suggest that PRM treatment has significant therapeutic implications for the improvement of post-SCI outcome.
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Chen ZH, Han YY, Shang YJ, Zhuang SY, Huang JN, Wu BY, Li CH. Cordycepin Ameliorates Synaptic Dysfunction and Dendrite Morphology Damage of Hippocampal CA1 via A1R in Cerebral Ischemia. Front Cell Neurosci 2022; 15:783478. [PMID: 35002628 PMCID: PMC8740211 DOI: 10.3389/fncel.2021.783478] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 12/01/2021] [Indexed: 01/18/2023] Open
Abstract
Cordycepin exerted significant neuroprotective effects and protected against cerebral ischemic damage. Learning and memory impairments after cerebral ischemia are common. Cordycepin has been proved to improve memory impairments induced by cerebral ischemia, but its underlying mechanism has not been revealed yet. The plasticity of synaptic structure and function is considered to be one of the neural mechanisms of learning and memory. Therefore, we investigated how cordycepin benefits dendritic morphology and synaptic transmission after cerebral ischemia and traced the related molecular mechanisms. The effects of cordycepin on the protection against ischemia were studied by using global cerebral ischemia (GCI) and oxygen-glucose deprivation (OGD) models. Behavioral long-term potentiation (LTP) and synaptic transmission were observed with electrophysiological recordings. The dendritic morphology and histological assessment were assessed by Golgi staining and hematoxylin-eosin (HE) staining, respectively. Adenosine A1 receptors (A1R) and adenosine A2A receptors (A2AR) were evaluated with western blotting. The results showed that cordycepin reduced the GCI-induced dendritic morphology scathing and behavioral LTP impairment in the hippocampal CA1 area, improved the learning and memory abilities, and up-regulated the level of A1R but not A2AR. In the in vitro experiments, cordycepin pre-perfusion could alleviate the hippocampal slices injury and synaptic transmission cripple induced by OGD, accompanied by increased adenosine content. In addition, the protective effect of cordycepin on OGD-induced synaptic transmission damage was eliminated by using an A1R antagonist instead of A2AR. These findings revealed that cordycepin alleviated synaptic dysfunction and dendritic injury in ischemic models by modulating A1R, which provides new insights into the pharmacological mechanisms of cordycepin for ameliorating cognitive impairment induced by cerebral ischemia.
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Affiliation(s)
- Zhao-Hui Chen
- School of Life Science, South China Normal University, Guangzhou, China
| | - Yuan-Yuan Han
- School of Life Science, South China Normal University, Guangzhou, China.,Panyu Central Hospital, Guangzhou, China
| | - Ying-Jie Shang
- School of Life Science, South China Normal University, Guangzhou, China
| | - Si-Yi Zhuang
- School of Life Science, South China Normal University, Guangzhou, China
| | - Jun-Ni Huang
- School of Life Science, South China Normal University, Guangzhou, China
| | - Bao-Yan Wu
- Ministry of Education (MOE) Key Laboratory of Laser Life Science, Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, China
| | - Chu-Hua Li
- School of Life Science, South China Normal University, Guangzhou, China
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Ma D, Huang R, Guo K, Zhao Z, Wei W, Gu L, Li L, Zhang L. Cornel Iridoid Glycoside Protects Against STAT1-Dependent Synapse and Memory Deficits by Increasing N-Methyl-D-aspartate Receptor Expression in a Tau Transgenic Mice. Front Aging Neurosci 2021; 13:671206. [PMID: 34113246 PMCID: PMC8185567 DOI: 10.3389/fnagi.2021.671206] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/13/2021] [Indexed: 12/14/2022] Open
Abstract
P301S transgenic mice are an animal model of tauopathy and Alzheimer’s disease (AD), exhibiting tau pathology and synaptic dysfunction. Cornel iridoid glycoside (CIG) is an active ingredient extracted from Cornus officinalis, a traditional Chinese herb. In the present study, the purpose was to investigate the effects and mechanisms of CIG on tau pathology and synaptic dysfunction using P301S transgenic mice. The results showed that intragastric administration of CIG for 3.5 months improved cognitive impairments and the survival rate of P301S mice. Electrophysiological recordings and transmission electron microscopy study showed that CIG improved synaptic plasticity and increased the ultrastructure and number of synapse. Moreover, CIG increased the expression levels of N-methyl-D-aspartate receptors (NMDAR) subunits GluN1, GluN2A, and GluN2B, and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluA1. We inferred that the major mechanism of CIG involving in the regulation of synaptic dysfunctions was inhibiting the activation of Janus kinase-2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) signaling pathway and alleviating STAT1-induced suppression of NMDAR expressions. Based on our findings, we thought CIG might be a promising candidate for the therapy of tauopathy such as AD.
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Affiliation(s)
- Denglei Ma
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Rui Huang
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Kaiwen Guo
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Zirun Zhao
- Renaissance School of Medicine at Stony Brook University, Stony Brook, NY, United States
| | - Weipeng Wei
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Lihong Gu
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Lin Li
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
| | - Lan Zhang
- Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Department of Pharmacy, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital of Capital Medical University, Beijing, China
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5
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Zhao L, Zhang L, Zhu W, Chen H, Ding Y, Cui G. Inhibition of microRNA-203 protects against traumatic brain injury induced neural damages via suppressing neuronal apoptosis and dementia-related molecues. Physiol Behav 2021; 228:113190. [PMID: 33002497 DOI: 10.1016/j.physbeh.2020.113190] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 07/30/2020] [Accepted: 09/26/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Traumatic brain injury (TBI) can lead to cognitive dysfunction and motor dysfunction. TBI is a potential risk factor for subsequent dementia. Hyperphosphorylation of Tau and ApoE4 has been found in patients with TBI. A significant increase in miR-203 was also found in the peripheral blood of TBI mice. Thus, we hypothesize that miR-203 inhibitor protects against neuronal damage and behavioral deficits by inhibition of Tau phosphorylation, ApoE4 expression and apoptosis. METHODS TBI mice were induced and treated with miR-203 inhibitor. Tau phosphorylation and ApoE4, hippocampal long-term potentiation (LTP), learning and memory, and motor function were separately detected by Western blot analysis, electrophysiology recording and behavioral assessments including Morris water maze test, beam-balance test, beam-walk test and rotarod test. Caspase-3 activity and bcl-2 expression were detected by ELISA. RESULTS TBI induction led to increased phosphorylation of Tau and ApoE4 expression. Administration of miR-203 inhibitor suppressed TBI induced ApoE4 expression and Tau hyperphosphorylation, rescued TBI mediated hippocampal LTP deficits and hippocampus dependent learning and memory dysfunction. miR-203 inhibitor treatment also improved motor function. In addition, miR-203 inhibitor treatment inhibited neuronal apoptosis by inhibiting caspase-3 activity and increasing bcl-2 expression. CONCLUSION miR-203 inhibitor treatment can rescue TBI-induced neural damage by inhibiting neuronal apoptosis and dementia markers like ApoE4 expression and Tau phosphorylation.
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Affiliation(s)
- Li Zhao
- Department of Pharmacy, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai 264000, Shangdong, China
| | - Lei Zhang
- Department of Pharmacy, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai 264000, Shangdong, China
| | - Wei Zhu
- Department of Neurosurgery, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai 264000, Shangdong, China
| | - Hongguang Chen
- Department of Neurosurgery, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai 264000, Shangdong, China
| | - Yuexia Ding
- Department of Pharmacy, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai 264000, Shangdong, China
| | - Guangqiang Cui
- Department of Neurosurgery, the Affiliated Yantai Yuhuangding Hospital of Qingdao University, No. 20 Yuhuangding East Road, Yantai 264000, Shangdong, China.
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6
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Gelman S, Palma J, Ghavami A. Axonal Conduction Velocity in CA1 Area of Hippocampus is Reduced in Mouse Models of Alzheimer's Disease. J Alzheimers Dis 2020; 77:1383-1388. [PMID: 32925062 DOI: 10.3233/jad-200661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The timing of action potentials arrival at synaptic terminals partially determines integration of synaptic inputs and is important for information processing in the CNS. Therefore, axonal conduction velocity (VC) is a salient parameter, influencing the timing of synaptic inputs. Even small changes in VC may disrupt information coding in networks requiring accurate timing. We recorded compound action potentials in hippocampal slices to measure VC in three mouse models of Alzheimer's disease. We report an age-dependent reduction in VC in area CA1 in two amyloid-β precursor protein transgenic mouse models, line 41 and APP/PS1, and in a tauopathy model, rTg4510.
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7
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Zhu W, Zhao L, Li T, Xu H, Ding Y, Cui G. Docosahexaenoic acid ameliorates traumatic brain injury involving JNK-mediated Tau phosphorylation signaling. Neurosci Res 2020; 157:44-50. [DOI: 10.1016/j.neures.2019.07.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 07/14/2019] [Accepted: 07/22/2019] [Indexed: 10/26/2022]
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de Amorim VCM, Júnior MSO, da Silva AB, David JM, David JPL, de Fátima Dias Costa M, Butt AM, da Silva VDA, Costa SL. Agathisflavone modulates astrocytic responses and increases the population of neurons in an in vitro model of traumatic brain injury. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1921-1930. [PMID: 32444988 DOI: 10.1007/s00210-020-01905-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 05/10/2020] [Indexed: 12/20/2022]
Abstract
Traumatic brain injury (TBI) is a critical health problem worldwide, with a high incidence rate and potentially severe long-term consequences. Depending on the level of mechanical stress, astrocytes react with complex morphological and functional changes known as reactive astrogliosis. In cases of severe tissue injury, astrocytes proliferate in the area immediately adjacent to the lesion to form the glial scar, which is a major barrier to neuronal regeneration in the central nervous system. The flavonoid agathisflavone has been shown to have neuroprotective, neurogenic, and immunomodulatory effects and could have beneficial effects in situations of TBI. In this study, we investigated the effects of agathisflavone on modulating the responses of astrocytes and neurons to injury, using the in vitro scratch wound model of TBI in primary cultures of rat cerebral cortex. In control conditions, the scratch wound induced an astroglial injury response, characterized by upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy, together with the reduction in proportion of neurons within the lesion site. Treatment with agathisflavone (1 μM) decreased astroglial GFAP expression and hypertrophy and induced an increase in the number of neurons and neurite outgrowth into the lesion site. Agathisflavone also induced increased expression of the neurotrophic factors NGF and GDNF, which are associated with the neuroprotective profile of glial cells. These results demonstrate that in an in vitro model of TBI, the flavonoid agathisflavone modulates the astrocytic injury response and glial scar formation, stimulating neural recomposition.
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Affiliation(s)
- Vanessa Cristina Meira de Amorim
- Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon, Salvador, BA, 40100-902, Brazil
| | - Markley Silva Oliveira Júnior
- Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon, Salvador, BA, 40100-902, Brazil
| | - Alessandra Bispo da Silva
- Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon, Salvador, BA, 40100-902, Brazil
| | - Jorge M David
- Department of General and Inorganic Chemistry, Institute of Chemistry, Federal University of Bahia, R. Barão de Jeremoabo, Salvador, BA, 40170-115, Brazil
| | - Juceni Pereira Lima David
- Department of Medication, Faculty of Pharmacy, Federal University of Bahia, R. Barão de Jeremoabo, Salvador, BA, 40170-115, Brazil
| | - Maria de Fátima Dias Costa
- Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon, Salvador, BA, 40100-902, Brazil
| | - Arthur Morgan Butt
- School of Pharmacy and Biomedical Science, University of Portsmouth, Winston Churchill Avenue, Portsmouth, PO1 2UP, UK
| | - Victor Diogenes Amaral da Silva
- Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon, Salvador, BA, 40100-902, Brazil
| | - Silvia Lima Costa
- Department of Biochemistry and Biophysics, Institute of Health Sciences, Federal University of Bahia, Av. Reitor Miguel Calmon, Salvador, BA, 40100-902, Brazil.
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Escobar I, Xu J, Jackson CW, Perez-Pinzon MA. Altered Neural Networks in the Papez Circuit: Implications for Cognitive Dysfunction after Cerebral Ischemia. J Alzheimers Dis 2020; 67:425-446. [PMID: 30584147 PMCID: PMC6398564 DOI: 10.3233/jad-180875] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Cerebral ischemia remains a leading cause of mortality worldwide. Although the incidence of death has decreased over the years, surviving patients may suffer from long-term cognitive impairments and have an increased risk for dementia. Unfortunately, research aimed toward developing therapies that can improve cognitive outcomes following cerebral ischemia has proved difficult given the fact that little is known about the underlying processes involved. Nevertheless, mechanisms that disrupt neural network activity may provide valuable insight, since disturbances in both local and global networks in the brain have been associated with deficits in cognition. In this review, we suggest that abnormal neural dynamics within different brain networks may arise from disruptions in synaptic plasticity processes and circuitry after ischemia. This discussion primarily concerns disruptions in local network activity within the hippocampus and other extra-hippocampal components of the Papez circuit, given their role in memory processing. However, impaired synaptic plasticity processes and disruptions in structural and functional connections within the Papez circuit have important implications for alterations within the global network, as well. Although much work is required to establish this relationship, evidence thus far suggests there is a link. If pursued further, findings may lead toward a better understanding of how deficits in cognition arise, not only in cerebral ischemia, but in other neurological diseases as well.
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Affiliation(s)
- Iris Escobar
- Department of Neurology, Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, USA.,Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jing Xu
- Department of Neurology, Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, USA.,Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Charles W Jackson
- Department of Neurology, Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, USA.,Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Miguel A Perez-Pinzon
- Department of Neurology, Cerebral Vascular Disease Research Laboratories, University of Miami Miller School of Medicine, Miami, FL, USA.,Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
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Wang SS, Jia J, Wang Z. Mesenchymal Stem Cell-Derived Extracellular Vesicles Suppresses iNOS Expression and Ameliorates Neural Impairment in Alzheimer's Disease Mice. J Alzheimers Dis 2019; 61:1005-1013. [PMID: 29254100 DOI: 10.3233/jad-170848] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs)-derived extracellular vesicles (EVs) have been reported to exhibit therapeutic effects in various animal models of neurological diseases, such as stroke and hypoxic-ischemic brain injury. OBJECTIVE The present study investigated the potential beneficial effect of MSC-derived EVs in an animal model of Alzheimer's disease (AD). METHODS APP/PS1 mice and their non-transgenic littermates (WT) received intracerebroventricle injection of MSC-derived EVs once per two days for two weeks. Then novel object recognition and water maze tasks were carried out to measure the cognitive behaviors. Electrophysiological tests were carried out to measure hippocampal synaptic plasticity. Inducible nitric oxide synthase (iNOS) mRNA and protein levels were measured by qRT-PCR and western blotting in primary cultured neurons treated with amyloid-β peptide (Aβ) or prepared from APP/PS1 mice. RESULTS Treatment with MSC-derived EVs alleviates exogenous Aβ-induced iNOS mRNA and protein expression. In cultured primary neurons prepared from APP/PS1 pups, iNOS mRNA and protein levels were significantly reduced when treated with MSC-derived EVs. MSC-derived EVs improved cognitive behavior, rescued impairment of CA1 synaptic transmission, and long-term potentiation in APP/PS1 mice. CONCLUSION MSC-derived EVs possessed beneficial effects in a mouse model of AD, probably by suppressing Aβ induced iNOS expression.
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Affiliation(s)
- Shan-Shan Wang
- Department of Geriatric Neurology, Nanlou Clinical Division, Chinese PLA General Hospital, Beijing, P.R. China
| | - Jianjun Jia
- Department of Geriatric Neurology, Nanlou Clinical Division, Chinese PLA General Hospital, Beijing, P.R. China
| | - Zhenfu Wang
- Department of Geriatric Neurology, Nanlou Clinical Division, Chinese PLA General Hospital, Beijing, P.R. China
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11
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Dobolyi A, Lékó AH. The insulin-like growth factor-1 system in the adult mammalian brain and its implications in central maternal adaptation. Front Neuroendocrinol 2019; 52:181-194. [PMID: 30552909 DOI: 10.1016/j.yfrne.2018.12.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Revised: 11/04/2018] [Accepted: 12/11/2018] [Indexed: 12/15/2022]
Abstract
Our knowledge on the bioavailability and actions of insulin-like growth factor-1 (IGF-1) has markedly expanded in recent years as novel mechanisms were discovered on IGF binding proteins (IGFBPs) and their ability to release IGF-1. The new discoveries allowed a better understanding of the endogenous physiological actions of IGF-1 and also its applicability in therapeutics. The focus of the present review is to summarize novel findings on the neuronal, neuroendocrine and neuroplastic actions of IGF-1 in the adult brain. As most of the new regulatory mechanisms were described in the periphery, their implications on brain IGF system will also be covered. In addition, novel findings on the effects of IGF-1 on lactation and maternal behavior are described. Based on the enormous neuroplastic changes related to the peripartum period, IGF-1 has great but largely unexplored potential in maternal adaptation of the brain, which is highlighted in the present review.
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Affiliation(s)
- Arpád Dobolyi
- MTA-ELTE Laboratory of Molecular and Systems Neurobiology, Department of Physiology and Neurobiology, Hungarian Academy of Sciences and Eötvös Loránd University, Budapest, Hungary.
| | - András H Lékó
- MTA-ELTE Laboratory of Molecular and Systems Neurobiology, Department of Physiology and Neurobiology, Hungarian Academy of Sciences and Eötvös Loránd University, Budapest, Hungary; Laboratory of Neuromorphology, Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary; Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
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12
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Gelman S, Palma J, Tombaugh G, Ghavami A. Differences in Synaptic Dysfunction Between rTg4510 and APP/PS1 Mouse Models of Alzheimer's Disease. J Alzheimers Dis 2018; 61:195-208. [PMID: 29154272 PMCID: PMC5836403 DOI: 10.3233/jad-170457] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2017] [Indexed: 12/15/2022]
Abstract
Genetically modified mice have provided insights into the progression and pathology of Alzheimer's disease (AD). Here, we have examined two mouse models of AD: the rTg4510 mouse, which overexpresses mutant human Tau gene, and the APP/PS1 mouse, which overexpresses mutant human genes for amyloid precursor protein and presenilin 1. Both models exhibit deficits in hippocampal function, but comparative analyses of these deficits are sparse. We used extracellular field potential recordings in hippocampal slices to study basal synaptic transmission (BST), paired-pulse facilitation (PPF), and long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapses in both models. We found that 6-7, but not 2-3-month-old rTg4510 mice exhibited reduced pre-synaptic activation (fiber volley (FV) amplitude, ∼50%) and field excitatory post-synaptic potential (fEPSP) slope (∼40%) compared to wild-type controls. In contrast to previous reports, BST, when controlled for FV amplitude, was not altered in rTg4510. APP/PS1 mice (2-3 mo and 8-10 mo) had unchanged FV amplitude compared to wild-type controls, while fEPSP slope was reduced by ∼34% in older mice, indicating a deficit in BST. PPF was unchanged in 8-10-month-old APP/PS1 mice, but was reduced in 6-7-month-old rTg4510 mice. LTP was reduced only in older rTg4510 and APP/PS1 mice. Our data suggest that BST deficits appear earlier in APP/PS1 than in rTg4510, which exhibited no BST deficits at the ages tested. However, FV and synaptic plasticity deficits developed earlier in rTg4510. These findings highlight fundamental differences in the progression of synaptic pathology in two genetically distinct models of AD.
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Affiliation(s)
- Simon Gelman
- Psychogenics, Inc., Montvale, NJ and Tarrytown, NY, USA
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Zhang B, Wei K, Li X, Hu R, Qiu J, Zhang Y, Yao W, Zhang C, Zhu C. Upregulation of Cdh1 signaling in the hippocampus attenuates brain damage after transient global cerebral ischemia in rats. Neurochem Int 2017; 112:166-178. [PMID: 28711656 DOI: 10.1016/j.neuint.2017.07.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 07/07/2017] [Accepted: 07/10/2017] [Indexed: 01/27/2023]
Abstract
Cerebral ischemia is a major cause of brain dysfunction. The E3 ubiquitin ligase anaphase-promoting complex and its coactivator Cdh1 have been reported to be involved in the regulation of neuronal survival, differentiation, axonal growth and synaptic development in the central nervous system. However, its role in the ischemic brain and the underlying mechanisms remain poorly understood. The present study aimed to investigate the effects of Cdh1 overexpression on the ischemic rat brain by direct intra-hippocampal injection of lentivirus-delivered Cdh1 before transient global cerebral ischemia reperfusion. Spatial memory acquisition and retention were assessed using a Morris water maze task. Neuronal damage, glial activation, oxidative stress and the synaptic ultrastructure were also examined. The results indicated that a recombinant Cdh1-encoding lentiviral vector can upregulate the expression of Cdh1 in the rat hippocampus. Cdh1 overexpression increased the survival rates of rats, reversed the abnormal accumulation of cyclin B1, alleviated neuronal death, inhibited glial activation, mitigated oxidative stress, modulated synaptic plasticity and improved neurological deficits caused by ischemia. Our study indicates that targeting the Cdh1 signaling pathway in the hippocampus may provide a promising therapeutic strategy for the clinical treatment of transient global cerebral ischemia.
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Affiliation(s)
- Bo Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Kai Wei
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Xuan Li
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Rong Hu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Jin Qiu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Yue Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Wenlong Yao
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Chuanhan Zhang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China
| | - Chang Zhu
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
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Huffman J, Hoffmann C, Taylor GT. Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes. World J Diabetes 2017; 8:45-55. [PMID: 28265342 PMCID: PMC5320748 DOI: 10.4239/wjd.v8.i2.45] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 09/24/2016] [Accepted: 11/22/2016] [Indexed: 02/05/2023] Open
Abstract
Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1 (IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sex-hormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinase signaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through similar signaling cascades. Future research on both neuroprotection and diabetes should include androgens into the interplay of IGF1 and sex hormones.
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Ya BL, Li HF, Wang HY, Wu F, Xin Q, Cheng HJ, Li WJ, Lin N, Ba ZH, Zhang RJ, Liu Q, Li YN, Bai B, Ge F. 5-HMF attenuates striatum oxidative damage via Nrf2/ARE signaling pathway following transient global cerebral ischemia. Cell Stress Chaperones 2017; 22:55-65. [PMID: 27812888 PMCID: PMC5225060 DOI: 10.1007/s12192-016-0742-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 10/10/2016] [Accepted: 10/11/2016] [Indexed: 12/20/2022] Open
Abstract
Recent studies have shown 5-hydroxymethyl-2-furfural (5-HMF) has favorable biological effects, and its neuroprotection in a variety of neurological diseases has been noted. Our previous study showed that treatment of 5-HMF led to protection against permanent global cerebral ischemia. However, the underlying mechanisms in cerebral ischemic injury are not fully understood. This study was conducted to investigate the neuroprotective effect of 5-HMF and elucidate the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway mechanism in the striatum after transient global cerebral ischemia. C57BL/6 mice were subjected to bilateral common carotid artery occlusion for 20 min and sacrificed 24 h after reperfusion. 5-HMF (12 mg/kg) or an equal volume of vehicle was intraperitoneally injected 30 min before ischemia and 5 min after the onset of reperfusion. At 24 h after reperfusion, neurological function was evaluated by neurological disability status scale, locomotor activity test and inclined beam walking test. Histological injury of the striatum was observed by cresyl violet staining and terminal deoxynucleotidyl transferase (TdT)-mediated dNTP nick end labeling (TUNEL) staining. Oxidative stress was evaluated by the carbonyl groups introduced into proteins, and malondialdehyde (MDA) levels. An enzyme-linked immunosorbent assay (ELISA)-based measurement was used to detect Nrf2 DNA binding activity. Nrf2 and its downstream ARE pathway protein expression such as heme oxygenase-1, NAD (P)H:quinone oxidoreductase 1, glutamate-cysteine ligase catalytic subunit and glutamate-cysteine ligase modulatory subunit were detected by western blot. Our results showed that 5-HMF treatment significantly ameliorated neurological deficits, reduced brain water content, attenuated striatum neuronal damage, decreased the carbonyl groups and MDA levels, and activated Nrf2/ARE signaling pathway. Taken together, these results demonstrated that 5-HMF exerted significant antioxidant and neuroprotective effects following transient cerebral ischemia, possibly through the activation of the Nrf2/ARE signaling pathway.
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Affiliation(s)
- Bai-Liu Ya
- Department of Physiology, Jining Medical University, 16 He-hua Street, Bei-hu District, Jining, Shandong, 272067, People's Republic of China
| | - Hong-Fang Li
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong, 272129, People's Republic of China
| | - Hai-Ying Wang
- Department of Physiology, Jining Medical University, 16 He-hua Street, Bei-hu District, Jining, Shandong, 272067, People's Republic of China
| | - Fei Wu
- Department of Physiology, Jining Medical University, 16 He-hua Street, Bei-hu District, Jining, Shandong, 272067, People's Republic of China
| | - Qing Xin
- Department of Physiology, Jining Medical University, 16 He-hua Street, Bei-hu District, Jining, Shandong, 272067, People's Republic of China
| | - Hong-Ju Cheng
- Department of Physiology, Jining Medical University, 16 He-hua Street, Bei-hu District, Jining, Shandong, 272067, People's Republic of China
| | - Wen-Juan Li
- School of Forensic and Laboratory Medicine, Jining Medical University, Jining, Shandong, 272067, People's Republic of China
| | - Na Lin
- Department of Physiology, Jining Medical University, 16 He-hua Street, Bei-hu District, Jining, Shandong, 272067, People's Republic of China
| | - Zai-Hua Ba
- Department of Physiology, Jining Medical University, 16 He-hua Street, Bei-hu District, Jining, Shandong, 272067, People's Republic of China
| | - Ru-Juan Zhang
- Jining First People's Hospital, Jining, Shandong, 272011, People's Republic of China
| | - Qian Liu
- School of Clinical Medicine, Jining Medical University, Jining, Shandong, 272067, People's Republic of China
| | - Ya-Nan Li
- School of Clinical Medicine, Jining Medical University, Jining, Shandong, 272067, People's Republic of China
| | - Bo Bai
- Department of Physiology, Jining Medical University, 16 He-hua Street, Bei-hu District, Jining, Shandong, 272067, People's Republic of China
| | - Feng Ge
- Department of Physiology, Jining Medical University, 16 He-hua Street, Bei-hu District, Jining, Shandong, 272067, People's Republic of China.
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Global ischemia induces lysosomal-mediated degradation of mTOR and activation of autophagy in hippocampal neurons destined to die. Cell Death Differ 2016; 24:317-329. [PMID: 27935582 PMCID: PMC5299717 DOI: 10.1038/cdd.2016.140] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Revised: 09/08/2016] [Accepted: 10/14/2016] [Indexed: 12/18/2022] Open
Abstract
The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, autophagy, translation, and survival. Dysregulation of mTOR signaling is associated with cancer, diabetes, and autism. However, a role for mTOR signaling in neuronal death is not well delineated. Here we show that global ischemia triggers a transient increase in mTOR phosphorylation at S2448, whereas decreasing p-mTOR and functional activity in selectively vulnerable hippocampal CA1 neurons. The decrease in mTOR coincides with an increase in biochemical markers of autophagy, pS317-ULK-1, pS14-Beclin-1, and LC3-II, a decrease in the cargo adaptor p62, and an increase in autophagic flux, a functional readout of autophagy. This is significant in that autophagy, a catabolic process downstream of mTORC1, promotes the formation of autophagosomes that capture and target cytoplasmic components to lysosomes. Inhibitors of the lysosomal (but not proteasomal) pathway rescued the ischemia-induced decrease in mTOR, consistent with degradation of mTOR via the autophagy/lysosomal pathway. Administration of the mTORC1 inhibitor rapamycin or acute knockdown of mTOR promotes autophagy and attenuates ischemia-induced neuronal death, indicating an inverse causal relation between mTOR, autophagy, and neuronal death. Our findings identify a novel and previously unappreciated mechanism by which mTOR self-regulates its own levels in hippocampal neurons in a clinically relevant model of ischemic stroke.
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Dyer AH, Vahdatpour C, Sanfeliu A, Tropea D. The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity. Neuroscience 2016; 325:89-99. [DOI: 10.1016/j.neuroscience.2016.03.056] [Citation(s) in RCA: 192] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 02/29/2016] [Accepted: 03/24/2016] [Indexed: 02/07/2023]
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