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Kong G, Liu J, Wang J, Yu X, Li C, Deng M, Liu M, Wang S, Tang C, Xiong W, Fan J. Engineered Extracellular Vesicles Modified by Angiopep-2 Peptide Promote Targeted Repair of Spinal Cord Injury and Brain Inflammation. ACS NANO 2025; 19:4582-4600. [PMID: 39853366 PMCID: PMC11803916 DOI: 10.1021/acsnano.4c14675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/06/2025] [Accepted: 01/07/2025] [Indexed: 01/26/2025]
Abstract
Engineered extracellular vesicles play an increasingly important role in the treatment of spinal cord injury. In order to prepare more effective engineered extracellular vesicles, we biologically modified M2 microglia. Angiopep-2 (Ang2) is an oligopeptide that can target the blood-brain barrier. Through single-cell sequencing and immunofluorescence experiments, we confirmed that the expression of LRP-1, the targeted receptor of Ang2, was elevated after spinal cord injury. Subsequently, we integrated the Ang2 peptide segment into M2 microglia to obtain Ang2-EVs, which could successfully target the site of spinal cord injury. However, in order to improve the function of Ang2-EVs, we pretreated M2 microglia with melatonin, which has anti-inflammatory effects, to obtain M-Ang2-EVs. The results of single-nucleus sequencing of the mouse spinal cord verified that neurons and OPCs gradually transformed into subtypes related to nerve repair functions after treatment with M-Ang2-EVs. This is consistent with the sequencing and enrichment analysis of miRNAs contained in M-Ang2-EVs. We further verified through experiments that M-Ang2-EVs can promote microglia/macrophages to phagocytose sphingomyelin, promote axon remyelination and axon elongation, and maintain the integrity of the blood-spinal barrier. Since Ang2 can also target the blood-brain barrier, we found that M-Ang2-EVs can also reduce brain inflammation that results from spinal cord injury. Our study applied the Angiopep-2 peptide to spinal cord injury to enhance the targeting of injured cells, and successfully construct engineered extracellular vesicles that can target the spinal cord injury site and the brain.
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Affiliation(s)
- Guang Kong
- Department
of Orthopedics, Xijing Hospital, Fourth
Military Medical University, Xi’an 710000 Shaanxi, China
| | - Jie Liu
- Department
of Orthopedics, The Affiliated Taizhou People’s
Hospital of Nanjing Medical University, Taizhou School of Clinical
Medicine, Nanjing Medical University, 366 Taihu Road, Taizhou 225300 Jiangsu, China
| | - Juan Wang
- Department
of Human Anatomy, School of Basic Medicine, Nanjing Medical University, Nanjing 210000 Jiangsu, China
| | - Xiaohu Yu
- Department
of Orthopedics, The First Affiliated Hospital
of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210000 Jiangsu, China
| | - Cong Li
- Department
of Orthopedics, The First Affiliated Hospital
of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210000 Jiangsu, China
| | - Mingyang Deng
- Department
of Orthopedics, The First Affiliated Hospital
of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210000 Jiangsu, China
| | - Minhao Liu
- Department
of Orthopedics, The First Affiliated Hospital
of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210000 Jiangsu, China
| | - Siming Wang
- Department
of Orthopedics, The First Affiliated Hospital
of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210000 Jiangsu, China
| | - Chunming Tang
- Department
of Pharmaceutics, School of Pharmacy, Nanjing
Medical University, 300
Guangzhou Road, Nanjing 210000 Jiangsu, China
| | - Wu Xiong
- Department
of Orthopedics, The First Affiliated Hospital
of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210000 Jiangsu, China
| | - Jin Fan
- Department
of Orthopedics, The First Affiliated Hospital
of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210000 Jiangsu, China
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Nagagata BA, Brito G, Ornellas F, Mandarim-de-Lacerda CA, Aguila MB. Melatonin supplementation in obese mothers reduces hypothalamic inflammation and enhances thermogenesis in mice progeny. J Nutr Biochem 2024; 128:109625. [PMID: 38521130 DOI: 10.1016/j.jnutbio.2024.109625] [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: 01/18/2024] [Revised: 03/07/2024] [Accepted: 03/18/2024] [Indexed: 03/25/2024]
Abstract
Maternal obesity might induce obesity and metabolic alterations in the progeny. The study aimed to determine the effect of supplementing obese mothers with Mel (Mel) on thermogenesis and inflammation. C57BL/6 female mice (mothers) were fed from weaning to 12 weeks control diet (C, 17% kJ as fat) or a high-fat diet (HF, 49% kJ as fat) and then matted with male mice fed the control diet. Melatonin (10 mg/kg daily) was supplemented to mothers during gestation and lactation, forming the groups C, CMel, HF, and HFMel (n = 10/group). Twelve-week male offspring were studied (plasma biochemistry, immunohistochemistry, protein, and gene expressions at the hypothalamus - Hyp, subcutaneous white adipose tissue - sWAT, and interscapular brown adipose tissue - iBAT). Comparing HFMel vs. HF offspring, fat deposits and plasmatic proinflammatory markers decreased. Also, HFMel showed decreased Hyp proinflammatory markers and neuropeptide Y (anabolic) expression but improved proopiomelanocortin (catabolic) expression. Besides, HFMel sWAT adipocytes changed to a beige phenotype with-beta-3 adrenergic receptor and uncoupling protein-1 activation, concomitant with browning genes activation, triggering the iBAT thermogenic activity. In conclusion, compelling evidence indicated the beneficial effects of supplementing obese mothers with Mel on the health of their mature male offspring. Mel led to sWAT browning-related gene enhancement, increased iBAT thermogenis, and mitigated hypothalamic inflammation. Also, principal component analysis of the data significantly separated the untreated obese mother progeny from the progeny of treated obese mothers. If confirmed in humans, the findings encourage a future guideline recommending Mel supplementation during pregnancy and breastfeeding.
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Affiliation(s)
- Brenda A Nagagata
- Metabolism section, Laboratory of Morphometry, Metabolism and Cardiovascular Disease, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil; Nutrition section, Laboratory of Morphometry, Metabolism and Cardiovascular Disease, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Gabrielle Brito
- Metabolism section, Laboratory of Morphometry, Metabolism and Cardiovascular Disease, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Carlos A Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Marcia Barbosa Aguila
- Laboratory of Morphometry, Metabolism and Cardiovascular Disease, Biomedical Center, Institute of Biology, The University of the State of Rio de Janeiro, Rio de Janeiro, Brazil
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Esrefoğlu M, Kalkan TK, Karatas E, Elibol B, Hekimoglu ER, Karakaya Cimen FB, Yay AH. Hepatoprotective actions of melatonin by mainly modulating oxidative status and apoptosis rate in lipopolysaccharide-induced liver damage. Immunopharmacol Immunotoxicol 2024; 46:161-171. [PMID: 38051589 DOI: 10.1080/08923973.2023.2291751] [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: 07/28/2023] [Accepted: 12/02/2023] [Indexed: 12/07/2023]
Abstract
AIM One of the serious complications of sepsis is liver damage and liver failure. This study aimed to evaluate the protective and therapeutic potential of melatonin in rats with lipopolysaccharide-induced sepsis. MAIN METHODS Female Spraque-Dawley rats received single a dose of 7.5 mg/kg lipopolysaccharide in saline to create a 24-h sepsis model. One of the other groups received melatonin at a dose of 10 mg/kg/day beginning 1 week before sepsis induction to the end of the experiment. The melatonin group received the same doses of melatonin for the same duration but not lipopolysaccharide. The vehicle group received the same doses of saline, the vehicle of melatonin, for the same duration. Twenty-four hours after the last injection, the rats were decapitated. By appropriate histochemical, immunohistochemical, biochemical, and molecular techniques, anti-necrotic, anti-apoptotic, anti-necroptotic, anti-inflammatory, and antioxidant effects of melatonin were assessed. KEY FINDINGS Lipopolysaccharide has disrupted liver functions by inducing oxidative stress, inflammation, necrotic, apoptotic, and necroptotic cell death, thus disrupting liver functions. Melatonin was found to be beneficial in terms of inhibiting the intrinsic pathway of apoptosis and tissue oxidant levels, stimulating tissue antioxidant enzyme levels, and restoring hepatocyte functions. SIGNIFICANCE Melatonin, at those doses and duration, was found to be hepatoprotective by mainly modulating oxidative status and apoptosis rate, however, failed to significantly reduce histopathological damage. We suggest that longer-term melatonin administration may produce anti-inflammatory and anti-necrotic effects as well.
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Affiliation(s)
- Mukaddes Esrefoğlu
- Department of Histology and Embryology, Faculty of Medicine, Bezmialem Vakıf University, Istanbul, Turkey
| | - Tugce Kubra Kalkan
- Department of Histology and Embryology, Faculty of Medicine, Kirşehir Ahi Evran University, Kırşehir, Turkey
| | - Ersin Karatas
- Department of Medical Services and Techniques, Patnos Vocation School, Ağrı İbrahim Çeçen University, Ağrı, Turkey
| | - Birsen Elibol
- Department of Medical Biology, Istanbul Medeniyet University, Istanbul, Turkey
| | - Emine Rumeysa Hekimoglu
- Department of Histology and Embryology, Faculty of Medicine, Bezmialem Vakıf University, Istanbul, Turkey
| | - Fatma Bedia Karakaya Cimen
- Department of Histology and Embryology, Faculty of Medicine, Bezmialem Vakıf University, Istanbul, Turkey
| | - Arzu Hanim Yay
- Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
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Li H, Zhou B, Wu J, Zhang Y, Zhang W, Doherty M, Deng X, Wang N, Xie D, Wang Y, Xie H, Li C, Wei J, Lei G, Zeng C. Melatonin is a potential novel analgesic agent for osteoarthritis: Evidence from cohort studies in humans and preclinical research in rats. J Pineal Res 2024; 76:e12945. [PMID: 38348943 DOI: 10.1111/jpi.12945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 01/05/2024] [Accepted: 01/21/2024] [Indexed: 02/15/2024]
Abstract
Melatonin exhibits potential for pain relief and long-term safety profile. We examined the analgesic effects of oral melatonin on osteoarthritis (OA) and investigated the underlying mechanism. Using data from a UK primary care database, we conducted a cohort study in individuals with OA to compare the number of oral analgesic prescriptions and the risk of knee/hip replacement between melatonin initiators and hypnotic benzodiazepines (i.e., active comparator) initiators using quantile regression models and Cox-proportional hazard models, respectively. To elucidate causation, we examined the effects of melatonin on pain behaviors and explored several metabolites that may serve as potential regulatory agents of melatonin in the monoiodoacetate rat model of OA. Using data from another community-based cohort study, that is, the Xiangya OA Study, we verified the association between the key serum metabolite and incident symptomatic knee OA. Compared with the hypnotic benzodiazepines cohort (n = 8135), the melatonin cohort (n = 813) had significantly fewer subsequent prescriptions of oral analgesics (50th percentile: 5 vs. 7, 75th percentile: 19 vs. 29, and 99th percentile: 140 vs. 162) and experienced a lower risk of knee/hip replacement (hazard ratio = 0.47, 95% Cl: 0.30-0.73) during the follow-up period. In rats, oral melatonin alleviated pain behaviors and increased serum levels of glycine. There was an inverse association between baseline serum glycine levels and the risk of incident symptomatic knee OA in humans (n = 760). In conclusion, our findings indicate that oral melatonin shows significant potential to be a novel treatment for OA pain. The potential role of glycine in its analgesic mechanism warrants further investigation.
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Affiliation(s)
- Hui Li
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Bin Zhou
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Jing Wu
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Yuqing Zhang
- Department of Medicine, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- The Mongan Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Weiya Zhang
- Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK
- Pain Centre Versus Arthritis, University of Nottingham, Nottingham, UK
| | - Michael Doherty
- Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK
- Pain Centre Versus Arthritis, University of Nottingham, Nottingham, UK
| | - Xinjia Deng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
| | - Ning Wang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Dongxing Xie
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Yilun Wang
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
| | - Hui Xie
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Changjun Li
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Department of Endocrinology, Endocrinology Research Center, Xiangya Hospital, Central South University, Changsha, China
| | - Jie Wei
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
| | - Guanghua Lei
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Chao Zeng
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Aging-related Bone and Joint Diseases Prevention and Treatment, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
- Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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González-Flores D, López-Pingarrón L, Castaño MY, Gómez MÁ, Rodríguez AB, García JJ, Garrido M. Melatonin as a Coadjuvant in the Treatment of Patients with Fibromyalgia. Biomedicines 2023; 11:1964. [PMID: 37509603 PMCID: PMC10377739 DOI: 10.3390/biomedicines11071964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 07/08/2023] [Accepted: 07/10/2023] [Indexed: 07/30/2023] Open
Abstract
Fibromyalgia syndrome (FMS) is a chronic widespread pain syndrome that is accompanied by fatigue, sleep disturbances, anxiety, depression, lack of concentration, and neurocognitive impairment. As the currently available drugs are not completely successful against these symptoms and frequently have several side effects, many scientists have taken on the task of looking for nonpharmacological remedies. Many of the FMS-related symptoms have been suggested to be associated with an altered pattern of endogenous melatonin. Melatonin is involved in the regulation of several physiological processes, including circadian rhythms, pain, mood, and oxidative as well as immunomodulatory balance. Preliminary clinical studies have propounded that the administration of different doses of melatonin to patients with FMS can reduce pain levels and ameliorate mood and sleep disturbances. Moreover, the total antioxidant capacity, 6-sulfatoxymelatonin and urinary cortisol levels, and other biological parameters improve after the ingestion of melatonin. Recent investigations have proposed a pathophysiological relationship between mitochondrial dysfunction, oxidative stress, and FMS by looking at certain proteins involved in mitochondrial homeostasis according to the etiopathogenesis of this syndrome. These improvements exert positive effects on the quality of life of FMS patients, suggesting that the use of melatonin as a coadjuvant may be a successful strategy for the management of this syndrome.
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Affiliation(s)
- David González-Flores
- Department of Anatomy, Cell Biology and Zoology, Science Faculty, University of Extremadura, 06006 Badajoz, Spain
- Neuroimmunophysiology and Chrononutrition Research Group, University of Extremadura, 06006 Badajoz, Spain
| | - Laura López-Pingarrón
- Oxidative Stress and Aging Research Group, Department of Pharmacology, Physiology, Legal and Forensic Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - María Yolanda Castaño
- Neuroimmunophysiology and Chrononutrition Research Group, University of Extremadura, 06006 Badajoz, Spain
- Department of Nursing, Merida University Center, University of Extremadura, 06006 Badajoz, Spain
| | - María Ángeles Gómez
- Neuroimmunophysiology and Chrononutrition Research Group, University of Extremadura, 06006 Badajoz, Spain
- Department of Physiology, Science Faculty, University of Extremadura, 06006 Badajoz, Spain
| | - Ana B Rodríguez
- Neuroimmunophysiology and Chrononutrition Research Group, University of Extremadura, 06006 Badajoz, Spain
- Department of Physiology, Science Faculty, University of Extremadura, 06006 Badajoz, Spain
| | - Joaquín J García
- Oxidative Stress and Aging Research Group, Department of Pharmacology, Physiology, Legal and Forensic Medicine, University of Zaragoza, 50009 Zaragoza, Spain
| | - María Garrido
- Neuroimmunophysiology and Chrononutrition Research Group, University of Extremadura, 06006 Badajoz, Spain
- Department of Physiology, Science Faculty, University of Extremadura, 06006 Badajoz, Spain
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Katariya C, Malaiappan S. Melatonin as preemptive analgesic for intraoperative pain. Bioinformation 2023; 19:5-9. [PMID: 37720297 PMCID: PMC10504520 DOI: 10.6026/97320630019005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 09/19/2023] Open
Abstract
Several anti-inflammatory and analgesic drugs have been used to reduce pain and discomfort during periodontal surgeries. This study evaluates the efficacy of using melatonin and ketorolac for pain prevention during open-flap debridement surgery. This prospective randomized controlled trial was performed in patients who presented with chronic periodontitis after non-surgical periodontal therapy, requiring flap surgery. Group 1: Flap surgery following non-surgical periodontal therapy after one month with no oral administration of analgesic. Group 2: Flap surgery following non-surgical periodontal therapy after one month with oral administration of Ketorolac 400mg one hour prior to the surgery. Group 3: Flap surgery following non-surgical periodontal therapy after one month with oral administration of 2 mg Melatonin one hour prior to the surgery. VAS and FLACC score along with blood pressure, SPO2 and heart rate. Statistical analysis was done using SPSS software. The intragroup comparisons (control-test drug) demonstrated that melatonin and ketorolac showed positive preemptive effect which compared to the control with mean differences significantly different from zero. However, when melatonin and ketorolac were compared there was no significant difference in postoperative pain among patients. The adoption of a preemptive medication protocol using either melatonin or ketorolac may be considered effective for pain and discomfort prevention during and post open-flap debridement surgeries. Melatonin showed similar effect to gold standard ketorolac in terms of its preemptive analgesic effect additional to having anti-inflammatory effect. Further studies are required to standardize the protocol for using melatonin as preemptive analgesic for dental surgical procedures.
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Affiliation(s)
- Chanchal Katariya
- Department of Periodontics, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, India
| | - Sankari Malaiappan
- Department of Periodontics, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, India
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Pang Y, Li Y, Zhang Y, Wang H, Lang J, Han L, Liu H, Xiong X, Gu L, Wu X. Effects of inflammation and oxidative stress on postoperative delirium in cardiac surgery. Front Cardiovasc Med 2022; 9:1049600. [PMID: 36505383 PMCID: PMC9731159 DOI: 10.3389/fcvm.2022.1049600] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/07/2022] [Indexed: 11/23/2022] Open
Abstract
The past decade has witnessed unprecedented medical progress, which has translated into cardiac surgery being increasingly common and safe. However, complications such as postoperative delirium remain a major concern. Although the pathophysiological changes of delirium after cardiac surgery remain poorly understood, it is widely thought that inflammation and oxidative stress may be potential triggers of delirium. The development of delirium following cardiac surgery is associated with perioperative risk factors. Multiple interventions are being explored to prevent and treat delirium. Therefore, research on the potential role of biomarkers in delirium as well as identification of perioperative risk factors and pharmacological interventions are necessary to mitigate the development of delirium.
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Affiliation(s)
- Yi Pang
- Bengbu Medical College, Bengbu, Anhui, China
| | - Yuntao Li
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yonggang Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Hongfa Wang
- Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Junhui Lang
- Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Liang Han
- Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - He Liu
- Department of Anesthesiology, The Affiliated Huzhou Hospital, Zhejiang University School of Medicine, Huzhou Central Hospital, Huzhou, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaomin Wu
- Center for Rehabilitation Medicine, Department of Anesthesiology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China,*Correspondence: Xiaomin Wu,
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Li Y, Hung SW, Zhang R, Man GCW, Zhang T, Chung JPW, Fang L, Wang CC. Melatonin in Endometriosis: Mechanistic Understanding and Clinical Insight. Nutrients 2022; 14:nu14194087. [PMID: 36235740 PMCID: PMC9572886 DOI: 10.3390/nu14194087] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/27/2022] [Accepted: 09/27/2022] [Indexed: 11/16/2022] Open
Abstract
Endometriosis is defined as the development of endometrial glands and stroma outside the uterine cavity. Pathophysiology of this disease includes abnormal hormone profiles, cell survival, migration, invasion, angiogenesis, oxidative stress, immunology, and inflammation. Melatonin is a neuroendocrine hormone that is synthesized and released primarily at night from the mammalian pineal gland. Increasing evidence has revealed that melatonin can be synthesized and secreted from multiple extra-pineal tissues where it regulates immune response, inflammation, and angiogenesis locally. Melatonin receptors are expressed in the uterus, and the therapeutic effects of melatonin on endometriosis and other reproductive disorders have been reported. In this review, key information related to the metabolism of melatonin and its biological effects is summarized. Furthermore, the latest in vitro and in vivo findings are highlighted to evaluate the pleiotropic functions of melatonin, as well as to summarize its physiological and pathological effects and treatment potential in endometriosis. Moreover, the pharmacological and therapeutic benefits derived from the administration of exogenous melatonin on reproductive system-related disease are discussed to support the potential of melatonin supplements toward the development of endometriosis. More clinical trials are needed to confirm its therapeutic effects and safety.
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Affiliation(s)
- Yiran Li
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Sze-Wan Hung
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Ruizhe Zhang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Gene Chi-Wai Man
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Tao Zhang
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jacqueline Pui-Wah Chung
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Lanlan Fang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- Correspondence: (L.F.); (C.-C.W.); Tel.: +86-371-6691-3635 (L.F.); +852-3505-4267 (C.-C.W.)
| | - Chi-Chiu Wang
- Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
- Laboratory of Reproduction and Development, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China
- Chinese University of Hong Kong-Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
- Correspondence: (L.F.); (C.-C.W.); Tel.: +86-371-6691-3635 (L.F.); +852-3505-4267 (C.-C.W.)
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Anti-Inflammatory Comparison of Melatonin and Its Bromobenzoylamide Derivatives in Lipopolysaccharide (LPS)-Induced RAW 264.7 Cells and Croton Oil-Induced Mice Ear Edema. Molecules 2021; 26:molecules26144285. [PMID: 34299559 PMCID: PMC8304993 DOI: 10.3390/molecules26144285] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/29/2021] [Accepted: 07/13/2021] [Indexed: 11/16/2022] Open
Abstract
The pineal gland is a neuroendocrine organ that plays an important role in anti-inflammation through the hormone melatonin. The anti-inflammatory effects of melatonin and its derivatives have been reported in both in vitro and in vivo models. Our previous study reported the potent antioxidant and neuroprotective activities of bromobenzoylamide substituted melatonin. In silico analysis successfully predicted that melatonin bromobenzoylamid derivatives were protected from metabolism by CYP2A1, which is a key enzyme of the melatonin metabolism process. Therefore, the anti-inflammatory activities of melatonin and its bromobenzoylamide derivatives BBM and EBM were investigated in LPS-induced RAW 264.7 macrophages and croton oil-induced ear edema in mice. The experiments showed that BBM and EBM significantly reduced production of the inflammatory mediators interleukin-6 (IL-6), prostaglandin E2 (PGE2), and nitric oxide (NO) in a dose-dependent manner, but only slightly affected TNF-α in LPS-induced RAW 264.7 macrophages. This suggests that modifying melatonin at either the N1-position or the N-acetyl side chain affected production of NO, PGE2 and IL-6 in in vitro model. In the croton oil-induced mouse ear edema model, BBM, significantly decreased ear edema thickness at 2-4 h. It leads to conclude that bromobenzoylamide derivatives of melatonin may be one of the potential candidates for a new type of anti-inflammatory agent.
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Rathinavel T, Ammashi S, Shanmugam G. Analgesic and anti-inflammatory potential of Lupeol isolated from Indian traditional medicinal plant Crateva adansonii screened through in vivo and in silico approaches. J Genet Eng Biotechnol 2021; 19:62. [PMID: 33945040 PMCID: PMC8096876 DOI: 10.1186/s43141-021-00167-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/14/2021] [Indexed: 01/04/2023]
Abstract
BACKGROUND Lupeol, a triterpene bioactive compound isolated from Indian traditional plant Crateva adansonii acted as promising and alternative anti-inflammatory agent to treatments of diseases related to inflammation. The inflammatory process in the body serves an important function in the control and repair of injury. However, it is self-perpetuating in number of disease conditions, which must be prevented and treated. Worldwide most prescribing NASID drug shows severe side effects. Whereas drug from natural origin shows dual inhibition of inflammatory and analgesic target protein with more efficacy and less side effects than NSAID drugs. Our study aims to isolate and screen the analgesic and anti-inflammatory potential of lupeol, a pentacyclic triterpenoid isolated from leaf extract of Crateva adansonii belongs to Capparaceae family commonly used Indian traditional medicine for treating inflammatory diseases. RESULTS Methanol and chloroform leaf extracts (ME and CE) and lupeol fraction (LF) of plant Crateva adansonii is investigated through employing in vivo male Wistar albino rat model. Acute toxicity study of C. adansonii ME and CE leaf extracts reveals that no mortality and no behavioral changes in experimental animals up to 2 g/kg. So no lethal dose we consider two optimal doses 200 and 400 mg of plant leaf extracts for in vivo inflammatory and analgesic study. In vivo acute and chronic anti-inflammatory activity was carried out through carrageenan-induced rat paw edema and cotton pellet-induced granuloma models. LF (100 mg/kg, oral route) of Crateva adansonii evoked highest percentage of inflammation inhibition (50 and 33.96% respectively) in both in vivo acute and chronic inflammation model among all tested samples (ME and CE 200 mg and 400 mg/kg, oral route) including reference standard (10 mg/kg, oral route) indomethacin. Carrageenan-challenged experimental animals were screened for one inflammatory marker enzyme myeloperoxidase (MPO), inflammatory products such as Prostaglandrin E2 (PGE2), and eight different cytokines markers (TNFα, IL-6, IFN γ, IL-1α, IL-1β, MCP-1, Rantes, and MIP) associated with inflammation reveals that LF (100 mg/kg, oral route) of Crateva adansonii shows prominent anti-inflammatory activity than reference standard indomethacin (10 mg/kg, oral route) over all these biological tested parameters. In vivo analgesic assays such as hot plate assay and acetic acid-induced writhing assay revealed that LF (100 mg/kg, oral route) possesses significant analgesic activity (11.60 s and 69.05%) when compared with standard drug pentazocine(10 mg/kg, oral route). Finally, we made an in silico screening of lupeol against analgesic (nAChR) and anti-inflammatory (COX-2) target proteins reveals that lupeol possess highest binding affinity with nAChR and COX-2 target proteins (- 8.5 and - 9.0 Kcal/mol) over the reference standard pentazocine and indomethacin (- 7.0 and - 8.4 Kcal/mol) respectively. CONCLUSION The present study result provides a pharmacological evidences for analgesic and anti-inflammatory potential of lupeol isolated from Indian traditional plant Crateva adansonii act as a multi-target agent with immense anti-inflammatory potential targeting key molecules of inflammation such as MPO, PGE2, and eight pro-inflammatory cytokine markers. Outcome of present study is to find promising anti-inflammatory bioactive agents from the cheapest Indian traditional medicinal plant sources useful for pharmaceutical industries.
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Affiliation(s)
| | - Subramanian Ammashi
- Department of Biochemistry, Rajah Serfoji Government College (Autonomous), Thanjavur, Tamil Nadu, 613 005, India
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Cluster headache pathophysiology - insights from current and emerging treatments. Nat Rev Neurol 2021; 17:308-324. [PMID: 33782592 DOI: 10.1038/s41582-021-00477-w] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2021] [Indexed: 02/01/2023]
Abstract
Cluster headache is a debilitating primary headache disorder that affects approximately 0.1% of the population worldwide. Cluster headache attacks involve severe unilateral pain in the trigeminal distribution together with ipsilateral cranial autonomic features and a sense of agitation. Acute treatments are available and are effective in just over half of the patients. Until recently, preventive medications were borrowed from non-headache indications, so management of cluster headache is challenging. However, as our understanding of cluster headache pathophysiology has evolved on the basis of key bench and neuroimaging studies, crucial neuropeptides and brain structures have been identified as emerging treatment targets. In this Review, we provide an overview of what is known about the pathophysiology of cluster headache and discuss the existing treatment options and their mechanisms of action. Existing acute treatments include triptans and high-flow oxygen, interim treatment options include corticosteroids in oral form or for greater occipital nerve block, and preventive treatments include verapamil, lithium, melatonin and topiramate. We also consider emerging treatment options, including calcitonin gene-related peptide antibodies, non-invasive vagus nerve stimulation, sphenopalatine ganglion stimulation and somatostatin receptor agonists, discuss how evidence from trials of these emerging treatments provides insights into the pathophysiology of cluster headache and highlight areas for future research.
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Abstract
Acquired limb loss, whether from accident or amputation, occurs with an incidence of greater than 175,000 per year in the United States. Current prevalence is estimated at greater than 1.5 million and is expected to double within 30 years. While many patients with amputations may have no significant pain or sensory issues after healing from the initial loss, one-quarter to one-half of patients may have ongoing difficulties with residual limb pain, phantom limb pain, or phantom limb sensation. This review explores the potential etiologies of those symptoms, as well as a variety of treatment options that a practitioner may consider when approaching this condition.
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Affiliation(s)
- Gary Stover
- Department of Physical Medicine & Rehabilitation, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nathan Prahlow
- Department of Physical Medicine & Rehabilitation, Indiana University School of Medicine, Indianapolis, IN, USA
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Gelfand AA, Ross AC, Irwin SL, Greene KA, Qubty WF, Allen IE. Melatonin for Acute Treatment of Migraine in Children and Adolescents: A Pilot Randomized Trial. Headache 2020; 60:1712-1721. [DOI: 10.1111/head.13934] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 07/06/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022]
Affiliation(s)
- Amy A. Gelfand
- Department of Neurology UCSF Child & Adolescent Headache Program San Francisco CA USA
| | - Alexandra C. Ross
- Department of Pediatrics UCSF Child & Adolescent Headache Program San Francisco CA USA
| | - Samantha L. Irwin
- Department of Neurology UCSF Child & Adolescent Headache Program San Francisco CA USA
| | - Kaitlin A. Greene
- Division of Pediatric Neurology Department of Pediatrics Oregon Health & Science University Portland OR USA
| | - William F. Qubty
- Pediatric Headache Program Dell Medical School University of Texas at Austin Austin TX USA
| | - I. Elaine Allen
- Department of Epidemiology & Biostatistics University of California San Francisco San Francisco CA USA
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Chitimus DM, Popescu MR, Voiculescu SE, Panaitescu AM, Pavel B, Zagrean L, Zagrean AM. Melatonin's Impact on Antioxidative and Anti-Inflammatory Reprogramming in Homeostasis and Disease. Biomolecules 2020; 10:biom10091211. [PMID: 32825327 PMCID: PMC7563541 DOI: 10.3390/biom10091211] [Citation(s) in RCA: 151] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/30/2020] [Accepted: 08/18/2020] [Indexed: 12/12/2022] Open
Abstract
There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body functions and homeostasis, with great impact in the peripartum period and adult life. Melatonin promotes adaptation through allostasis and stands out as an endogenous, dietary, and therapeutic molecule with important health benefits. The anti-inflammatory and antioxidant effects of melatonin are intertwined and are exerted throughout pregnancy and later during development and aging. Melatonin supplementation during pregnancy can reduce ischemia-induced oxidative damage in the fetal brain, increase offspring survival in inflammatory states, and reduce blood pressure in the adult offspring. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The most studied cardiovascular effects of melatonin are linked to hypertension and myocardial ischemia/reperfusion injury, while the most promising ones are linked to regaining control of metabolic syndrome components. In addition, there might be an emerging role for melatonin as an adjuvant in treating coronavirus disease 2019 (COVID 19). The present review summarizes and comments on important data regarding the roles exerted by melatonin in homeostasis and oxidative stress and inflammation related pathologies.
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Affiliation(s)
- Diana Maria Chitimus
- Division of Physiology and Neuroscience, Department of Functional Sciences, “Carol Davila” University of Medicine and Pharmacy, 010164 Bucharest, Romania; (D.M.C.); (S.E.V.); (B.P.); (L.Z.)
| | - Mihaela Roxana Popescu
- Department of Cardiology, “Carol Davila” University of Medicine and Pharmacy, Elias University Hospital, 010164 Bucharest, Romania;
| | - Suzana Elena Voiculescu
- Division of Physiology and Neuroscience, Department of Functional Sciences, “Carol Davila” University of Medicine and Pharmacy, 010164 Bucharest, Romania; (D.M.C.); (S.E.V.); (B.P.); (L.Z.)
| | - Anca Maria Panaitescu
- Department of Obstetrics and Gynecology, “Carol Davila” University of Medicine and Pharmacy, Filantropia Clinical Hospital, 010164 Bucharest, Romania;
| | - Bogdan Pavel
- Division of Physiology and Neuroscience, Department of Functional Sciences, “Carol Davila” University of Medicine and Pharmacy, 010164 Bucharest, Romania; (D.M.C.); (S.E.V.); (B.P.); (L.Z.)
| | - Leon Zagrean
- Division of Physiology and Neuroscience, Department of Functional Sciences, “Carol Davila” University of Medicine and Pharmacy, 010164 Bucharest, Romania; (D.M.C.); (S.E.V.); (B.P.); (L.Z.)
| | - Ana-Maria Zagrean
- Division of Physiology and Neuroscience, Department of Functional Sciences, “Carol Davila” University of Medicine and Pharmacy, 010164 Bucharest, Romania; (D.M.C.); (S.E.V.); (B.P.); (L.Z.)
- Correspondence:
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Profiling and Identification of Omeprazole Metabolites in Mouse Brain and Plasma by Isotope Ratio-Monitoring Liquid Chromatography-Mass Spectrometric Method. Life (Basel) 2020; 10:life10070115. [PMID: 32707673 PMCID: PMC7400457 DOI: 10.3390/life10070115] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/13/2020] [Accepted: 07/16/2020] [Indexed: 12/27/2022] Open
Abstract
Neuro–inflammation is known to be one of the pathogenesis for the degenerative central nervous system (CNS) disease. Recently various approaches for the treatment of brain diseases by controlling neuro-inflammation in the brain have been introduced. In this respect, there is a continuous demand for CNS drugs, which could be safer and more effective. Omeprazole, a well-known proton-pump inhibitor (PPI) is generally prescribed for the treatment of peptic ulcer. In addition to the anti-gastric acid secretion mechanism, recent studies showed that omeprazole or PPIs would likely have anti-inflammation effects in vitro and in vivo, but their effects on anti-inflammation in brain are still unknown. In this study, omeprazole and its metabolites in a mouse’s brain after various routes of administration have been explored by stable isotope ratio-patterning liquid chromatography–mass spectrometric method. First, a simple liquid chromatography–mass spectrometric (LC–MS) method was established for the quantification of omeprazole in mouse plasma and brain. After that, omeprazole and its stable isotope (D3–omeprazole) were concomitantly administered through various routes to mice in order to identify novel metabolites characteristically observed in the mouse brain and were analyzed using a different LC–MS method with information-dependent analysis (IDA) scan. With this unique approach, several new metabolites of omeprazole were identified by the mass difference between omeprazole and stable isotope in both brain and plasma samples. A total of seventeen metabolites were observed, and the observed metabolites were different from each administration route or each matrix (brain or plasma). The brain pharmacokinetic profiles and brain-to-plasma partition coefficient (Kp) were also evaluated in a satellite study. Overall, these results provide better insights to understand the CNS-related biological effects of omeprazole and its metabolites in vivo.
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Hemati K, Pourhanifeh MH, Dehdashtian E, Fatemi I, Mehrzadi S, Reiter RJ, Hosseinzadeh A. Melatonin and morphine: potential beneficial effects of co-use. Fundam Clin Pharmacol 2020; 35:25-39. [PMID: 32415694 DOI: 10.1111/fcp.12566] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 04/27/2020] [Accepted: 05/11/2020] [Indexed: 02/06/2023]
Abstract
Morphine is a potent analgesic agent used to control acute or chronic pain. Chronic administration of morphine results in analgesic tolerance, hyperalgesia, and other side effects including dependence, addiction, respiratory depression, and constipation, which limit its clinical usage. Therefore, identifying the new analgesics with fewer side effects which could increase the effect of morphine and reduce its side effects is crucial. Melatonin, a multifunctional molecule produced in the body, is known to play an important role in pain regulation. The strong anti-inflammatory effect of melatonin is suggested to be involved in the attenuation of the pain associated with inflammation. Melatonin also increases the anti-nociceptive actions of opioids, such as morphine, and reverses their tolerance through regulating several cellular signaling pathways. In this review, published articles evaluating the effect of the co-consumption of melatonin and morphine in different conditions were investigated. Our results show that melatonin has pain-killing properties when administered alone or in combination with other anti-nociceptive drugs. Melatonin decreases morphine consumption in different pathologies. Furthermore, attenuation of morphine intake can be accompanied by reduction of morphine-associated side-effects, including physical dependence, morphine tolerance, and morphine-related hyperalgesia. Therefore, it is reasonable to believe that the combination of melatonin with morphine could reduce morphine-induced tolerance and hyperalgesia, which may result from anti-inflammatory and antioxidant properties of melatonin. Overall, we underscore that, to further ameliorate patients' life quality and control their pain in various pathological conditions, melatonin deserves to be used with morphine by anesthesiologists in clinical practice.
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Affiliation(s)
- Karim Hemati
- Department of Anesthesiology, Iran University of Medical Sciences, Shahid Hemmat Highway, Tehran, 1449614535, Iran
| | - Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Ghotb-e-Ravandy Boulevard, Kashan, 8715988141, Iran
| | - Ehsan Dehdashtian
- School of Medicine, Iran University of Medical Sciences, IRAN, Shahid Hemmat Highway, Tehran, 1449614535, Iran
| | - Iman Fatemi
- Rafsanjan University of Medical Sciences, imam Ali Bolvard, Rafsanjan, 7719617996, Iran
| | - Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Shahid Hemmat Highway, Tehran, 1449614535, Iran
| | - Russel J Reiter
- Department of Cellular and Structural Biology, The University of Texas Health Science Center, 7703 Floyd Curl Drive, Mail Code 7762, San Antonio, TX, 78229-3900, USA
| | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Shahid Hemmat Highway, Tehran, 1449614535, Iran
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Koohsari M, Ahangar N, Mohammadi E, Shaki F. Ameliorative Effect of Melatonin Against Reproductive Toxicity of Tramadol in Rats via the Regulation of Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis-related Gene Expression Signaling Pathway. ADDICTION & HEALTH 2020; 12:118-129. [PMID: 32782734 PMCID: PMC7395930 DOI: 10.22122/ahj.v12i2.265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/22/2020] [Indexed: 11/09/2022]
Abstract
BACKGROUND The aim of the present study was to investigate the protective properties of melatonin (MT) against oxidative stress, mitochondrial dysfunction, and apoptosis induced by tramadol-reproductive toxicity in male rats. METHODS The rats were divided into the 7 groups of control, melatonin (1.5 mg/kg), tramadol (50 mg/kg), and melatonin (1, 1.5 and 2.5 mg/kg) administered 30 minutes before tramadol and vitamin C group (100 mg/kg). All injections were performed intraperitoneally. After administration for 3 consecutive weeks, the animals were killed and testis tissues were used for assessment of oxidative stress markers including lipid peroxidation (LPO), glutathione (GSH) content and protein carbonyl (PrC), and sperm analysis. Mitochondria were isolated from rat's testis using differential centrifugation technique and were studied in terms of mitochondrial viability, mitochondrial membrane potential (MMP), and mitochondrial swelling. The other part of the tissue sample was placed in RNA protector solution for assessment of Bax and Bcl-2 gene expression through real-time polymerase chain reaction (real-time PCR) assay. FINDINGS Tramadol caused a significant decline in epidermal sperm count, motility, and morphology, as well as a significant decrease in GSH level and mitochondrial function, and a significant evaluation of LPO, PrC, MMP, and mitochondrial swelling. In addition, tramadol induced a significant decrease in Bcl-2 gene expression, and increase in Bax gene expression. However, pretreatment of rats with MT improved sperm analysis, and testicular antioxidative status, and mitochondrial function. Furthermore, MT pretreatment regulated testicular Bcl-2 and Bax expressions. CONCLUSION Considering the protective effects of MT against reproductive toxicity induced by tramadol, this compound can be used as a possible agent for the prevention and treatment of tramadol-induced reproductive toxicity.
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Affiliation(s)
- Motahareh Koohsari
- Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute AND Department of Toxicology and Pharmacology, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nematollah Ahangar
- Department of Pharmacology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Ebrahim Mohammadi
- Environmental Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Fatemeh Shaki
- Pharmaceutical Sciences Research Center, Hemoglobinopathy Institute AND Department of Toxicology and Pharmacology, School of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
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Maitra S, Bhattacharya D, Das S, Bhattacharya S. Melatonin and its anti-glioma functions: a comprehensive review. Rev Neurosci 2020; 30:527-541. [PMID: 30645197 DOI: 10.1515/revneuro-2018-0041] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 09/07/2018] [Indexed: 01/20/2023]
Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is a naturally synthesized hormone secreted from the pineal gland in a variety of animals and is primarily involved in the regulation of the circadian rhythm, which is the natural cycle controlling sleep in organisms. Melatonin acts on specific receptors and has an important role in overall energy metabolism. This review encompasses several aspects of melatonin activity, such as synthesis, source, structure, distribution, function, signaling and its role in normal physiology. The review highlights the cellular signaling and messenger systems involved in melatonin's action on the body and their wider implications, the distribution and diverse action of different melatonin receptors in specific areas of the brain, and the pharmacological agonists and antagonists that have specific action on these melatonin receptors. This review also incorporates the antitumor effects of melatonin in considerable detail, emphasizing on melatonin's role as an adjuvant therapeutic agent in glioma treatment. We conclude that the diminishing levels of melatonin have significant debilitating effects on normal physiology and can also be associated with malignant conditions such as glioma. Based on the review of the available evidence, our study provides a broad platform for a better understanding of the specific roles of melatonin and serves as a starting point for further investigation into the therapeutic effect of melatonin in glioma as an adjuvant therapeutic agent.
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Affiliation(s)
- Sayantan Maitra
- Department of Health and Family Welfare, Institute of Pharmacy, Jalpaiguri 735101, Govt. of West Bengal, India
| | - Debanjan Bhattacharya
- Department of Neurosurgery, Winship Cancer Institute of Emory University, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Stabak Das
- Department of Health and Family Welfare, Institute of Pharmacy, Jalpaiguri 735101, Govt. of West Bengal, India
| | - Subhrajit Bhattacharya
- Department of Pharmacology, Rollins Research Center, Emory University School of Medicine, 1510 Cliffton Rd. NE, Atlanta, GA 30303-3073, USA
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Adam R, Kanakarajan S, Onyeakazi U, Columb M, Galley H. Phase II double-blind randomised controlled trial of exogenous administration of melatonin in chronic pain (DREAM-CP): a study protocol. BMJ Open 2020; 10:e034443. [PMID: 32184313 PMCID: PMC7076250 DOI: 10.1136/bmjopen-2019-034443] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
INTRODUCTION Chronic pain is prevalent, and approximately half of patients with chronic pain experience sleep disturbance. Exogenous melatonin is licensed to treat primary insomnia and there is some evidence for analgesic effects of melatonin.The aim of this study is to investigate the effects of oral melatonin (as Circadin) 2 mg at night in adults with severe non-malignant pain of at least 3 months' duration. METHODS AND ANALYSIS We will conduct a randomised double-blind placebo-controlled cross-over study. The primary outcome is sleep disturbance. Secondary outcomes are pain intensity, actigraphy, fatigue, reaction time testing, serum melatonin and endogenous opioid peptide levels along with patient views about study participation.We aim to recruit 60 patients with severe chronic pain (average pain intensity ≥7 on the Brief Pain Inventory (BPI)) from a tertiary referral pain clinic in Northeast Scotland. Participants will be randomised to receive melatonin (as modified release Circadin) 2 mg daily for 6 weeks or placebo, followed by a 4-week washout period, then 6 weeks treatment with the treatment they did not receive. Participants will complete the Verran Snyder-Halpern Sleep Scale, Pittsburgh Sleep Quality Index, Pain and Sleep Questionnaire 3-item index, BPI and psychomotor vigilance reaction time testing at 6 points over 20 weeks. Actigraphy watches will be used to provide objective measures of sleep duration and latency and other sleep measures and will prompt patients to report contemporaneous pain and fatigue scores daily.Cross-over analyses will include tests for effects of treatment, period, treatment-period interaction (carryover effect) and sequence. Within-patient effects and longitudinal data will be analysed using mixed linear models, accounting for potential confounders. ETHICS AND DISSEMINATION Approved by Office for Research Ethics Committees Northern Ireland, reference 19/NI/0007. Results will be published in peer-reviewed journals and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER ISRCTN12861060.
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Affiliation(s)
- Rosalind Adam
- Academic Primary Care, Institute of Applied Health Sciences, Aberdeen, UK
| | | | - Uzunma Onyeakazi
- The Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
| | - Malachy Columb
- Wythenshawe Hospital Acute Intensive Care Unit, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Helen Galley
- The Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
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Song TJ, Kim BS, Chu MK. Therapeutic role of melatonin in migraine prophylaxis: Is there a link between sleep and migraine? PROGRESS IN BRAIN RESEARCH 2020; 255:343-369. [DOI: 10.1016/bs.pbr.2020.05.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 04/12/2020] [Accepted: 05/01/2020] [Indexed: 12/13/2022]
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Al Kury LT, Zeb A, Abidin ZU, Irshad N, Malik I, Alvi AM, Khalil AAK, Ahmad S, Faheem M, Khan AU, Shah FA, Li S. Neuroprotective effects of melatonin and celecoxib against ethanol-induced neurodegeneration: a computational and pharmacological approach. Drug Des Devel Ther 2019; 13:2715-2727. [PMID: 31447548 PMCID: PMC6683968 DOI: 10.2147/dddt.s207310] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 06/27/2019] [Indexed: 12/17/2022] Open
Abstract
PURPOSE Melatonin and celecoxib are antioxidants and anti-inflammatory agents that exert protective effects in different experimental models. In this study, the neuroprotective effects of melatonin and celecoxib were demonstrated against ethanol-induced neuronal injury by in silico, morphological, and biochemical approaches. METHODS For the in silico study, 3-D structures were constructed and docking analysis performed. For in vivo studies, rats were treated with ethanol, melatonin, and celecoxib. Brain samples were collected for biochemical and morphological analysis. RESULTS Homology modeling was performed to build 3-D structures for IL1β), TNFα, TLR4, and inducible nitric oxide synthase. Structural refinement was achieved via molecular dynamic simulation and processed for docking and postdocking analysis. Further in vivo experiments showed that ethanol induced marked neuronal injury characterized by downregulated glutathione, glutathione S-transferase, and upregulated inducible nitric oxide synthase. Additionally, ethanol increased the expression of TNFα and IL1β. Finally, neuronal apoptosis was demonstrated in ethanol-intoxicated animals using caspase 3 and activated JNK staining. On the other hand, melatonin and celecoxib treatment ameliorated the biochemical and immunohistochemical alterations induced by ethanol. CONCLUSION These results demonstrated that ethanol induced neurodegeneration by activating inflammatory and apoptotic proteins in rat brain, while melatonin and celecoxib may protect rat brain by downregulating inflammatory and apoptotic markers.
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Affiliation(s)
- Lina T Al Kury
- College of Natural and Health Sciences, Zayed University, Abu Dhabi, United Arab Emirates
| | - Alam Zeb
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Zain Ul Abidin
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Nadeem Irshad
- Department of Pharmacy, Quaid-I-Azam University, Islamabad, Pakistan
| | - Imran Malik
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Arooj Mohsin Alvi
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | | | | | - Muhammad Faheem
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Arif-Ullah Khan
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Fawad Ali Shah
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan
| | - Shupeng Li
- State Key Laboratory of Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen518055, People’s Republic of China
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Peres MF, Valença MM, Amaral FG, Cipolla-Neto J. Current understanding of pineal gland structure and function in headache. Cephalalgia 2019; 39:1700-1709. [PMID: 31370669 DOI: 10.1177/0333102419868187] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE The pineal gland plays an important role in biological rhythms, circadian and circannual variations, which are key aspects in several headache disorders. OVERVIEW Melatonin, the main pineal secreting hormone, has been extensively studied in primary and secondary headache disorders. Altered melatonin secretion occurs in many headache syndromes. Experimental data show pineal gland and melatonin both interfere in headache animal models, decreasing trigeminal activation. Melatonin has been shown to regulate CGRP and control its release. DISCUSSION Melatonin has been used successfully as a treatment for migraine, cluster headaches and other headaches. There is a rationale for including the pineal gland as a relevant brain structure in the mechanisms of headache pathophysiology, and melatonin as a treatment option in primary headache.
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Affiliation(s)
- Mario Fp Peres
- Hospital Israelita Albert Einstein, Sao Paolo, Brazil.,Instituto de Psiquiatria, Hospital das Clínicas da Faculdade de Medicina da USP, Pernambuco, Brazil
| | | | | | - José Cipolla-Neto
- Instituto de Ciencias Biomédicas, Universidade de São Paulo, São Paulo, Brazil
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Salehi B, Sharopov F, Fokou PVT, Kobylinska A, Jonge LD, Tadio K, Sharifi-Rad J, Posmyk MM, Martorell M, Martins N, Iriti M. Melatonin in Medicinal and Food Plants: Occurrence, Bioavailability, and Health Potential for Humans. Cells 2019; 8:cells8070681. [PMID: 31284489 PMCID: PMC6678868 DOI: 10.3390/cells8070681] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 06/25/2019] [Accepted: 07/03/2019] [Indexed: 12/15/2022] Open
Abstract
Melatonin is a widespread molecule among living organisms involved in multiple biological, hormonal, and physiological processes at cellular, tissue, and organic levels. It is well-known for its ability to cross the blood–brain barrier, and renowned antioxidant effects, acting as a free radical scavenger, up-regulating antioxidant enzymes, reducing mitochondrial electron leakage, and interfering with proinflammatory signaling pathways. Detected in various medicinal and food plants, its concentration is widely variable. Plant generative organs (e.g., flowers, fruits), and especially seeds, have been proposed as having the highest melatonin concentrations, markedly higher than those found in vertebrate tissues. In addition, seeds are also rich in other substances (lipids, sugars, and proteins), constituting the energetic reserve for a potentially growing seedling and beneficial for the human diet. Thus, given that dietary melatonin is absorbed in the gastrointestinal tract and transported into the bloodstream, the ingestion of medicinal and plant foods by mammals as a source of melatonin may be conceived as a key step in serum melatonin modulation and, consequently, health promotion.
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Affiliation(s)
- Bahare Salehi
- Student Research Committee, School of Medicine, Bam University of Medical Sciences, Bam 44340847, Iran
| | - Farukh Sharopov
- Department of Pharmaceutical Technology, Avicenna Tajik State Medical University, 73400 Dushanbe, Tajikistan
| | | | - Agnieszka Kobylinska
- Laboratory of Plant Ecophysiology, Faculty of Biology and Environmental Protection, University of Lodz, 90-237 Lodz, Poland
| | - Lilian de Jonge
- Department of Nutrition and Food Studies, George Mason University, Fairfax, VA 22030, USA
| | - Kathryn Tadio
- Department of Nutrition and Food Studies, George Mason University, Fairfax, VA 22030, USA
| | - Javad Sharifi-Rad
- Zabol Medicinal Plants Research Center, Zabol University of Medical Sciences, Zabol 61615-585, Iran.
| | - Malgorzata M Posmyk
- Laboratory of Plant Ecophysiology, Faculty of Biology and Environmental Protection, University of Lodz, 90-237 Lodz, Poland.
| | - Miquel Martorell
- Department of Nutrition and Dietetics, Faculty of Pharmacy, University of Concepcion, Concepcion 4070386, Chile
| | - Natália Martins
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal.
| | - Marcello Iriti
- Department of Agricultural and Environmental Sciences, Milan State University, 20133 Milan, Italy.
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24
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Adnan M, Nazim Uddin Chy M, Mostafa Kamal ATM, Barlow JW, Faruque MO, Yang X, Uddin SB. Evaluation of anti-nociceptive and anti-inflammatory activities of the methanol extract of Holigarna caustica (Dennst.) Oken leaves. JOURNAL OF ETHNOPHARMACOLOGY 2019; 236:401-411. [PMID: 30703495 DOI: 10.1016/j.jep.2019.01.025] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2018] [Revised: 01/07/2019] [Accepted: 01/25/2019] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Holigarna caustica (Dennst.) is commonly used in traditional medicine to treat a variety of painful conditions such as eye irritation, inflammation, arthritis, skin diseases, cuts and wounds. AIM OF THE STUDY The present study was undertaken to investigate the anti-nociceptive and anti-inflammatory activities of the methanol extract of H. caustica leaves and to elucidate its possible mechanism(s) of action. MATERIALS AND METHODS Fresh leaves of H. caustica were collected, dried, and extracted with methanol (MEHC). MEHC was subjected to activity testing, using chemical-induced (acetic acid and formalin test) and heat-induced (hot plate and tail immersion test) pain models. To determine the possible mechanism behind the anti-nociceptive activity of MEHC, the opioid antagonist naltrexone was used to evaluate the involvement of opioid receptors in the case of formalin, hot plate and tail immersion tests, while the involvement of the cGMP and ATP-sensitive K+ channel pathways were assessed using methylene blue and glibenclamide respectively, in the acetic acid-induced writhing test. In parallel, the carrageenan-induced paw oedema model was used to determine the anti-inflammatory potential of the extract. Exploratory and motor behaviours were evaluated by the open-field test. Various bioactive compounds potentially responsible for the anti-nociceptive and anti-inflammatory activities were ascertained using GC-MS analysis. RESULTS MEHC showed strong, significant and dose-dependent anti-nociceptive activity in all chemical-induced and heat-induced pain models at all experimental doses. The association of opioid receptors with the observed anti-nociceptive effects was confirmed by using naltrexone. The cGMP and ATP-sensitive K+ channel pathway was also shown to be involved in the anti-nociceptive activity of MEHC. In addition, MEHC exhibited a dose-dependent inhibition of inflammatory oedema induced by carrageenan. MEHC was not connected with changes in either the locomotor activity or motor responses of mice. In a GC-MS analysis, 40 compounds were identified, among which twelve are documented bioactive compounds with potent analgesic and anti-inflammatory properties. CONCLUSIONS Our current study revealed that MEHC possesses strong central and peripheral anti-nociceptive as well as anti-inflammatory activity. It may also be concluded that both opioid receptors as well as the cGMP and ATP-sensitive K+ channel pathway are involved in the anti-nociceptive mechanism of MEHC. This study rationalizes the ethnomedicinal use of H. caustica leaves in various painful conditions.
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Affiliation(s)
- Md Adnan
- Pharmacognosy and Phytochemistry Lab, Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh; College of Biomedical Science, Department of Bio-Health Technology, Kangwon National University, Chuncheon 24341, Republic of Korea.
| | - Md Nazim Uddin Chy
- Pharmacognosy and Phytochemistry Lab, Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - A T M Mostafa Kamal
- Pharmacognosy and Phytochemistry Lab, Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh.
| | - James W Barlow
- Department of Chemistry, Royal College of Surgeons, Dublin, Ireland.
| | - Mohammad Omar Faruque
- Ethnobotany and Pharmacognosy Lab, Department of Botany, University of Chittagong, Chittagong 4331, Bangladesh.
| | - Xinzhou Yang
- School of Pharmaceutical Science, South-Central Universities for Nationalities, Wuhan, China.
| | - Shaikh Bokhtear Uddin
- Ethnobotany and Pharmacognosy Lab, Department of Botany, University of Chittagong, Chittagong 4331, Bangladesh.
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25
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Nabavi SM, Nabavi SF, Sureda A, Xiao J, Dehpour AR, Shirooie S, Silva AS, Baldi A, Khan H, Daglia M. Anti-inflammatory effects of Melatonin: A mechanistic review. Crit Rev Food Sci Nutr 2019; 59:S4-S16. [DOI: 10.1080/10408398.2018.1487927] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Affiliation(s)
- Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Seyed Fazel Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Antoni Sureda
- Grup de Nutrici_o Comunit_aria i Estr_es Oxidatiu and CIBEROBN (Physiopathology of Obesity and Nutrition), Universitat de les Illes Balears, Palma de E-07122 Mallorca, Spain
| | - Janbo Xiao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Control in Chinese Medicine, University of Macau, Macau SAR, China
| | - Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Samira Shirooie
- School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ana Sanches Silva
- National Institute for Agricultural and Veterinary Research (INIAV), I.P., Vairão, Vila do Conde, Portugal; Center for Study in Animal Science (CECA), ICETA, University of Oporto, Oporto, Portugal
| | - Alessandra Baldi
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Pavia, Italy
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan, Pakistan
| | - Maria Daglia
- Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, Pavia, Italy
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26
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Bora NS, Mazumder B, Mandal S, Bhutia YD, Das S, Karmakar S, Chattopadhyay P, Dwivedi SK. Protective effect of a topical sunscreen formulation fortified with melatonin against UV-induced photodermatitis: an immunomodulatory effect via NF-κB suppression. Immunopharmacol Immunotoxicol 2019; 41:130-139. [PMID: 30741582 DOI: 10.1080/08923973.2019.1566358] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Objective: Melatonin and pumpkin seed oil, along with US FDA approved UV filters were incorporated into a formulation for enhancement of UV protection by exerting an antioxidant effect. The objective of this study was to assess the protective effect of this formulation against ultraviolet (UV) radiation-induced photo dermatitis in rats, which is an established model to study the aetiopathogenic mechanisms in psoriasis vulgaris, as the former exhibits the same features to those of clinical psoriasis vulgaris in humans. Materials and methods: The animals were segregated into five groups (6/group) and all received their respective formulations dermally prior to chronic UV irradiation for 28 days. The test, placebo, and standard groups; received the test, placebo, and standard formulations respectively; whereas the positive control group received only UV radiation. A normal control group was also maintained. Disease and treatment status were analyzed using various techniques by euthanizing the rats after 28 days. Results: The test formulation was able to ameliorate the UV-induced increase in skin fold, epidermal thickness, and skin edema; inhibit the reduction of hydroxyproline content and incidence of LPO within the skin tissues of exposed animals. The formulation was also able to inhibit the release of proinflammatory cytokines; IFN-γ, IL-1β, IL-6, and TNF-α; and upregulation of NF-κB and COX-2 genes caused by chronic UV exposure. Conclusion: It can be stated that melatonin included in the newly formulated sunscreen was able to inhibit the induction of photodermatitis via immunoregulation of inflammatory cytokines along with NF-κB and COX-2 genes.
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Affiliation(s)
- Nilutpal Sharma Bora
- a Division of Pharmaceutical Technology , Defence Research Laboratory , Tezpur , India.,b Department of Pharmaceutical Sciences , Dibrugarh University , Dibrugarh , India
| | - Bhaskar Mazumder
- b Department of Pharmaceutical Sciences , Dibrugarh University , Dibrugarh , India
| | - Santa Mandal
- a Division of Pharmaceutical Technology , Defence Research Laboratory , Tezpur , India.,c School of Pharmaceutical Sciences , IFTM University , Moradabad , India
| | - Yangchen D Bhutia
- a Division of Pharmaceutical Technology , Defence Research Laboratory , Tezpur , India
| | - Sanghita Das
- a Division of Pharmaceutical Technology , Defence Research Laboratory , Tezpur , India
| | - Sanjeev Karmakar
- a Division of Pharmaceutical Technology , Defence Research Laboratory , Tezpur , India
| | | | - Sanjai K Dwivedi
- a Division of Pharmaceutical Technology , Defence Research Laboratory , Tezpur , India
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27
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Kukushkin ML, Poluektov MG. Current Views on Chronic Pain and Its Relationship to the State of Sleep. ACTA ACUST UNITED AC 2018. [DOI: 10.1007/s11055-018-0684-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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28
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Serhatlioglu I, Bilgin B, Kacar E, Ozcan S, Canpolat S, Ayar A, Kelestimur H, Ozcan M. Agomelatine modulates calcium signaling through protein kinase C and phospholipase C-mediated mechanisms in rat sensory neurons. J Cell Physiol 2018; 234:10741-10746. [PMID: 30443943 DOI: 10.1002/jcp.27748] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 10/22/2018] [Indexed: 01/06/2023]
Abstract
Agomelatine, a novel antidepressant exerting its effects through melatonergic and serotonergic systems, implicated to be effective against pain including neuropathic pain but without any knowledge of mechanism of action. To explore the possible role of agomelatine on nociceptive transmission at the peripheral level, the effects of agomelatine on intracellular calcium ([Ca2+ ]i ) signaling in peripheral neurons were investigated in cultured rat dorsal root ganglion (DRG) neurons. Using the fura-2-based calcium imaging technique, the effects of agomelatine on [Ca2+ ]i and roles of the second messenger-mediated pathways were assessed. Agomelatine caused [Ca2+ ]i signaling in a dose-dependent manner when tested at 10 and 100 μM concentration. Luzindole, a selective melatonin receptor antagonist, almost completely blocked the agomelatine-induced calcium signals. The agomelatine-induced calcium transients were also nearly abolished following pretreatment with the 100 ng/ml pertussis toxin, a Gi/o protein inhibitor. The stimulatory effects of agomelatine on [Ca2+ ]i transients were significantly reduced by applications of phospholipase C (PLC) and protein kinase C (PKC) blockers, 10 μM U73122, and 10 μM chelerythrine chloride, respectively. The obtained results of agomelatine-induced [Ca2+ ]i signals indicates that peripheral mechanisms are involved in analgesic effects of agomelatine. These mechanisms seems to involve G-protein-coupled receptor activation and PLC and PKC mediated mechanisms.
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Affiliation(s)
- Ihsan Serhatlioglu
- Department of Biophysics, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Batuhan Bilgin
- Department of Biophysics, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Emine Kacar
- Department of Physiology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Sibel Ozcan
- Department of Anesthesiology and Reanimation, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Sinan Canpolat
- Department of Physiology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Ahmet Ayar
- Department of Physiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
| | - Haluk Kelestimur
- Department of Physiology, Faculty of Medicine, Firat University, Elazig, Turkey
| | - Mete Ozcan
- Department of Biophysics, Faculty of Medicine, Firat University, Elazig, Turkey
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Melatonin Attenuates Pain Hypersensitivity and Decreases Astrocyte-Mediated Spinal Neuroinflammation in a Rat Model of Oxaliplatin-Induced Pain. Inflammation 2018; 40:2052-2061. [PMID: 28812173 DOI: 10.1007/s10753-017-0645-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Neuroinflammatory response in spinal dorsal horn has been demonstrated to be a critical factor in oxaliplatin-induced pain. Melatonin has been shown to have anti-inflammatory and anti-allodynia effects in both preclinical and clinical studies. In the present study, we investigated the role of systemic administration of melatonin on oxaliplatin-induced pain. Intraperitoneal (i.p.) injection with oxaliplatin induced significantly mechanical allodynia and thermal hyperalgesia. Melatonin (i.p.) significantly alleviated mechanical allodynia and thermal hyperalgesia in the oxaliplatin but not sham-treated rats. The attenuation of nociceptive response persisted at least to 3 days after melatonin injection, throughout the entire observing window. Immunohistochemistry showed that oxaliplatin induced a significant increase of glial fibrillary acidic protein (GFAP) immunodensities, which could be suppressed by melatonin. Western blotting showed that GFAP protein levels were significantly elevated in the oxaliplatin-vehicle group. Melatonin significantly decreased oxaliplatin-induced upregulation of GFAP expressions. Oxaliplatin injection also enhanced the messenger RNA (mRNA) expressions of cytokines including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) and chemokines including monocyte chemoattractant protein-1 (MCP-1) and monocyte inflammatory protein-1 (MIP-1α) in the spinal dorsal horn, which could be significantly repressed by melatonin. In vitro study showed that mRNA levels of TNF-α, IL-1β, MCP-1, and MIP-1α in primarily astrocytes were significantly increased after lipopolysaccharide (LPS, 1 μg/ml) stimulation. Melatonin (10 and 100 μM) greatly inhibited synthesis of these inflammatory mediators, in a dose-related manner. Conclusively, our data provide a novel implication of anti-nociceptive mechanism of melatonin in chemotherapy-related pain.
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30
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Hensley AL, Colley AR, Ross AE. Real-Time Detection of Melatonin Using Fast-Scan Cyclic Voltammetry. Anal Chem 2018; 90:8642-8650. [PMID: 29932641 DOI: 10.1021/acs.analchem.8b01976] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Melatonin is an important hormone whose functions span from regulating circadian rhythm in the brain to providing anti-inflammatory properties in the immune system. Melatonin secretion from the pineal gland is known; however, the mechanism of melatonin signaling in the immune system is not well understood. The lymph node is the hub of the immune system, and melatonin secretion from lymphocytes was proposed to be an important source specifically for regulating cytokine secretion. Methods exist to quantify the concentration of melatonin within biological samples; however, they often suffer from either a lack of selectivity for melatonin over common biological interferences or temporal resolution, which is not amenable to measuring real-time signaling dynamics. Here, we have characterized an electrochemical method for optimal melatonin detection with subsecond resolution using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. The oxidation peaks detected for melatonin were at 1.0, 1.1, and 0.6 V. Evidence for electrode fouling of the tertiary peak was present; therefore, an optimized waveform was developed scanning from 0.2 to 1.3 V at 600 V/s. The optimized waveform eliminated the detection of fouling products on the electrode with a 24 ± 10 nM limit of detection. Melatonin was distinguished between biological interferences, and codetection with the major synthetic precursor, serotonin, was possible. This method was used to detect melatonin in live lymph node slices and provides the first real-time measurements within the lymph node using FSCV. Real-time detection of melatonin dynamics could provide useful information on the mechanism of immunomodulation during inflammatory disease.
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Affiliation(s)
- Austin L Hensley
- Department of Chemistry , University of Cincinnati , Cincinnati , Ohio 45221 , United States
| | - Adam R Colley
- Department of Chemistry , University of Cincinnati , Cincinnati , Ohio 45221 , United States
| | - Ashley E Ross
- Department of Chemistry , University of Cincinnati , Cincinnati , Ohio 45221 , United States
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31
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Salma S, Baig SG, Hasan MMU, Ahmed S, Fatima SA. Analgesic and Anti-Inflammatory Effects of Phaseolus vulgaris L. Fixed Oil in Rodents. ACTA ACUST UNITED AC 2018. [DOI: 10.6000/1927-5129.2018.14.26] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
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Melatonin: A New-Generation Therapy for Reducing Chronic Pain and Improving Sleep Disorder-Related Pain. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1099:229-251. [DOI: 10.1007/978-981-13-1756-9_19] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Single Administration of Melatonin Modulates the Nitroxidergic System at the Peripheral Level and Reduces Thermal Nociceptive Hypersensitivity in Neuropathic Rats. Int J Mol Sci 2017; 18:ijms18102143. [PMID: 29036889 PMCID: PMC5666825 DOI: 10.3390/ijms18102143] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 10/05/2017] [Accepted: 10/12/2017] [Indexed: 12/15/2022] Open
Abstract
Neuropathic pain is a severe condition with unsatisfactory treatments. Melatonin, an indolamine, seems to be a promising molecule suitable for this purpose due to its well-known anti-inflammatory, analgesic, and antioxidant effects, as well as its modulation of the nitroxidergic system. Nevertheless, the data on its mechanism of action and potentialities are currently insufficient in this pathology, especially at the peripheral level. Thus, this work evaluated the effect of a single administration of melatonin in an established mononeuropathy pain model that monitors the behaviour and the changes in the nitroxidergic system in dorsal root ganglia and skin, which are affected by nervous impairment. Experiments were carried out on Sprague Dawley rats subdivided into the sham operated (control) and the chronic constriction injured animals, a model of peripheral neuropathic pain on sciatic nerve. Single administrations of melatonin (5–10 mg/kg) or vehicle were injected intraperitoneally on the 14th day after surgery, when the mononeuropathy was established. The animals were behaviourally tested for thermal hyperalgesia. The dorsal root ganglia and the plantar skin of the hind-paws were removed and processed for the immunohistochemical detection of neuronal and inducible nitric oxide synthases. The behavioural results showed an increase of withdrawal latency during the plantar test as early as 30 min after melatonin administration. The immunohistochemical results indicated a modulation of the nitroxidergic system both at dorsal root ganglia and skin level, permitting speculate on a possible mechanism of action. We showed that melatonin may be a possible therapeutic strategy in neuropathic pain.
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34
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Miranda-Páez A, Zamudio SR, Vázquez-León P, Sandoval-Herrera V, Villanueva-Becerril I, Carli G. Effect of melatonin injection into the periaqueductal gray on antinociception and tonic immobility in male rats. Horm Behav 2017; 89:23-29. [PMID: 27988316 DOI: 10.1016/j.yhbeh.2016.12.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2016] [Revised: 12/08/2016] [Accepted: 12/09/2016] [Indexed: 10/20/2022]
Abstract
Melatonin (MLT) is a neurohormone with significant involvement in several biological functions, of which antinociception and tonic immobility (TI) may be the key neurobehavioral components to survive in adverse conditions such as a predator attack. TI-induced antinociception can be elicited, facilitated, or increased through opioid and γ-aminobutyric acid (GABA) among other chemical mediators at several levels of the central nervous system, mainly in the periaqueductal gray (PAG). The aim of this study was to assess the effect of the microinjection of MLT into the main PAG regions that are related to different integrated defensive responses, namely dorsal (D) and ventrolateral (VL), on both antinociception through the tail-flick (TF) test and TI duration as single behavioral response and on combined behavioral responses (TF/TI). We found that the microinjection of MLT into the main PAG areas produced antinociception but did not affect the TI duration. The microinjection of MLT into the D-PAG decreased TF latency during TI in the combined trial (TF/TI), which implies that TI-induced antinociception was blocked. The microinjection of MLT into the VL-PAG maintained the antinociceptive capability of the TI without addition or increase in the antinociceptive effects, implying a permissive effect by MLT on the TI-induced antinociception. MLT administration into the D-PAG decreased the TI duration on the TF/TI, whereas MLT administration into the VL-PAG had the opposite effect of significantly increasing TI duration with the TF/TI trial.
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Affiliation(s)
- Abraham Miranda-Páez
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Wilfrido Massieu esq. Manuel Stampa s/n Col. Nueva Industrial Vallejo, CP 07738, Del. Gustavo A. Madero, México City, Mexico.
| | - Sergio R Zamudio
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Wilfrido Massieu esq. Manuel Stampa s/n Col. Nueva Industrial Vallejo, CP 07738, Del. Gustavo A. Madero, México City, Mexico
| | - Priscila Vázquez-León
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Wilfrido Massieu esq. Manuel Stampa s/n Col. Nueva Industrial Vallejo, CP 07738, Del. Gustavo A. Madero, México City, Mexico
| | - Vicente Sandoval-Herrera
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Wilfrido Massieu esq. Manuel Stampa s/n Col. Nueva Industrial Vallejo, CP 07738, Del. Gustavo A. Madero, México City, Mexico
| | - Ivan Villanueva-Becerril
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Wilfrido Massieu esq. Manuel Stampa s/n Col. Nueva Industrial Vallejo, CP 07738, Del. Gustavo A. Madero, México City, Mexico
| | - Giancarlo Carli
- Department of Medicine, Surgery and Neuroscience, University of Siena, Via A. Moro, 2, Room 10/127, 53100 Siena, Italy
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35
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Kukushkin ML, Poluektov MG. Contemporary approaches to the relationships between chronic pain and sleep. Zh Nevrol Psikhiatr Im S S Korsakova 2017; 117:19-27. [DOI: 10.17116/jnevro20171174219-27] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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36
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Kivrak Y, Karademir B, Aygun H, Ersan Y, Ari M, Karaahmet E, Yagci I. The Effect of Agomelatine on the Nociceptive System. ACTA ACUST UNITED AC 2016. [DOI: 10.5455/bcp.20130925022745] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Affiliation(s)
- Yuksel Kivrak
- Kafkas University School of Medicine, Department of Psychiatry, Kars-Turkey
| | | | - Hayati Aygun
- Kafkas University School of Medicine, Department of Orthopedics and Traumatology, Kars-Turkey
| | - Yusuf Ersan
- Kafkas University Faculty of Science and Art, Department of Biology, Kars-Turkey
| | - Mustafa Ari
- Mustafa Kemal University School of Medicine, Department of Psychiatry, Hatay-Turkey
| | - Elif Karaahmet
- Canakkale Onsekiz Mart University School of Medicine, Department of Psychiatry, Canakkale-Turkey
| | - Ibrahim Yagci
- Kafkas University School of Medicine, Department of Psychiatry, Kars-Turkey
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Gelfand AA, Goadsby PJ. The Role of Melatonin in the Treatment of Primary Headache Disorders. Headache 2016; 56:1257-66. [PMID: 27316772 PMCID: PMC5012937 DOI: 10.1111/head.12862] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Revised: 05/02/2016] [Accepted: 05/03/2016] [Indexed: 01/03/2023]
Abstract
OBJECTIVE To provide a summary of knowledge about the use of melatonin in the treatment of primary headache disorders. BACKGROUND Melatonin is secreted by the pineal gland; its production is regulated by the hypothalamus and increases during periods of darkness. METHODS We undertook a narrative review of the literature on the role of melatonin in the treatment of primary headache disorders. RESULTS There are randomized placebo-controlled trials examining melatonin for preventive treatment of migraine and cluster headache. For cluster headache, melatonin 10 mg was superior to placebo. For migraine, a randomized placebo-controlled trial of melatonin 3 mg (immediate release) was positive, though an underpowered trial of melatonin 2 mg (sustained release) was negative. Uncontrolled studies, case series, and case reports cover melatonin's role in treating tension-type headache, hypnic headache, hemicrania continua, SUNCT/SUNA and primary stabbing headache. CONCLUSIONS Melatonin may be effective in treating several primary headache disorders, particularly cluster headache and migraine. Future research should focus on elucidating the underlying mechanisms of benefit of melatonin in different headache disorders, as well as clarifying optimal dosing and formulation.
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Affiliation(s)
- Amy A. Gelfand
- UCSF Pediatric Headache, Department of Neurology, King’s College London, UK
| | - Peter J. Goadsby
- UCSF Pediatric Headache, Department of Neurology, King’s College London, UK
- NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, UK
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Chen WW, Zhang X, Huang WJ. Pain control by melatonin: Physiological and pharmacological effects. Exp Ther Med 2016; 12:1963-1968. [PMID: 27698681 PMCID: PMC5038497 DOI: 10.3892/etm.2016.3565] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 07/25/2016] [Indexed: 02/07/2023] Open
Abstract
Pain and anxiety are the most common neurological responses to many harmful or noxious stimuli and their management clinically is often challenging. Many of the frequently used morphine-based drugs, non-steroid anti-inflammatory drugs and acetaminophen, while efficient for treating pain, lead to patients suffering from several unwanted side effects. Melatonin, produced from the pineal body is a hormone of darkness, is involved in the control of circadian rhythms, and exerts a number of pharmacological effects. Melatonin mediates its actions through MT1/MT2 melatonin receptors on the cell membrane and also through RZR/ROR nuclear orphan receptors. Chronic pain syndromes are often associated with the desynchronization of circadian and biological rhythms, which also cause disturbances in the sleep-wake cycle. Melatonin-mediated analgesic effects seem to involve β-endorphins, GABA receptor, opioid receptors and the nitric oxide-arginine pathway. The effectiveness of melatonin as an analgesic and anxiolytic agent has been demonstrated in various animal models of pain and this led to the use of melatonin clinically in different pathological conditions and also in patients undergoing surgery. Melatonin was found to be effective in many of these cases as an anxiolytic and analgesic agent, indicating its clinical application.
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Affiliation(s)
- Wei-Wei Chen
- Department of Neurology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China
| | - Xia Zhang
- Department of Neurology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China
| | - Wen-Juan Huang
- Department of Neurology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China
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Kuedo Z, Sangsuriyawong A, Klaypradit W, Tipmanee V, Chonpathompikunlert P. Effects of Astaxanthin from Litopenaeus Vannamei on Carrageenan-Induced Edema and Pain Behavior in Mice. Molecules 2016; 21:382. [PMID: 27007359 PMCID: PMC6272999 DOI: 10.3390/molecules21030382] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 03/10/2016] [Accepted: 03/16/2016] [Indexed: 12/22/2022] Open
Abstract
Carrageenan produces both inflammation and pain when injected in mouse paws via enhancement of reactive oxygen species formation. We have investigated an effect of astaxanthin extracted from Litopenaeus vannamei in carrageenan-induced mice paw edema and pain. The current study demonstrates interesting effects from astaxanthin treatment in mice: an inhibition of paw edema induced in hind paw, an increase in mechanical paw withdrawal threshold and thermal paw withdrawal latency, and a reduction in the amount of myeloperoxidase enzyme and lipid peroxidation products in the paw. Furthermore the effect was comparable to indomethacin, a standard treatment for inflammation symptoms. Due to adverse effects of indomethacin on cardiovascular and gastrointestinal systems, our study suggests promising prospect of astaxanthin extract as an anti-inflammatory alternative against carrageenan-induced paw edema and pain behavior.
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Affiliation(s)
- Zulkiflee Kuedo
- Department of Physiology, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.
| | - Anantita Sangsuriyawong
- Center for Advanced Studies for Agriculture and Food, Kasetsart University, Bangkok 10900, Thailand.
| | - Wanwimol Klaypradit
- Center for Advanced Studies for Agriculture and Food, Kasetsart University, Bangkok 10900, Thailand.
| | - Varomyalin Tipmanee
- Department of Biomedical Sciences, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla 90110, Thailand.
| | - Pennapa Chonpathompikunlert
- Department of Physiology, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112, Thailand.
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Abstract
Melatonin is a neurohormone secreted by epiphysis and extrapineal structures. It performs several functions including chronobiotic, antioxidant, oncostatic, immune modulating, normothermal, and anxiolytic functions. Melatonin affects the cardiovascular system and gastrointestinal tract, participates in reproduction and metabolism, and body mass regulation. Moreover, recent studies have demonstrated melatonin efficacy in relation to pain syndromes. The present paper reviews the studies on melatonin use in fibromyalgia, headaches, irritable bowel syndrome, chronic back pain, and rheumatoid arthritis. The paper discusses the possible mechanisms of melatonin analgesic properties. On one hand, circadian rhythms normalization results in sleep improvement, which is inevitably disordered in chronic pain syndromes, and activation of melatonin adaptive capabilities. On the other hand, there is evidence of melatonin-independent analgesic effect involving melatonin receptors and several neurotransmitter systems.
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Affiliation(s)
- Andrei Danilov
- Department of Neurology, Postdegree Training Institute, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
| | - Julia Kurganova
- Department of Neurology, Postdegree Training Institute, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
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Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways. Pain 2015; 156:305-317. [PMID: 25599452 DOI: 10.1097/01.j.pain.0000460311.71572.5f] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Neuropathic pain is an important public health problem for which only a few treatments are available. Preclinical studies show that melatonin (MLT), a neurohormone acting on MT1 and MT2 receptors, has analgesic properties, likely through MT2 receptors. Here, we determined the effects of the novel selective MLT MT2 receptor partial agonist N-{2-([3-bromophenyl]-4-fluorophenylamino)ethyl}acetamide (UCM924) in 2 neuropathic pain models in rats and examined its supraspinal mechanism of action. In rat L5-L6 spinal nerve ligation and spared nerve injury models, UCM924 (20-40 mg/kg, subcutaneously) produced a prolonged antinociceptive effect that is : (1) dose-dependent and blocked by the selective MT2 receptor antagonist 4-phenyl-2-propionamidotetralin, (2) superior to a high dose of MLT (150 mg/kg) and comparable with gabapentin (100 mg/kg), but (3) without noticeable motor coordination impairments in the rotarod test. Using double staining immunohistochemistry, we found that MT2 receptors are expressed by glutamatergic neurons in the rostral ventrolateral periaqueductal gray. Using in vivo electrophysiology combined with tail flick, we observed that microinjection of UCM924 into the ventrolateral periaqueductal gray decreased tail flick responses, depressed the firing activity of ON cells, and activated the firing of OFF cells; all effects were MT2 receptor-dependent. Altogether, these data demonstrate that selective MT2 receptor partial agonists have analgesic properties through modulation of brainstem descending antinociceptive pathways, and MT2 receptors may represent a novel target in the treatment of neuropathic pain.
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Song L, Wu C, Zuo Y. Melatonin prevents morphine-induced hyperalgesia and tolerance in rats: role of protein kinase C and N-methyl-D-aspartate receptors. BMC Anesthesiol 2015; 15:12. [PMID: 25745356 PMCID: PMC4350305 DOI: 10.1186/1471-2253-15-12] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 01/20/2015] [Indexed: 02/05/2023] Open
Abstract
Background Morphine-induced hyperalgesia and tolerance significantly limits its clinical use in relieving acute and chronic pain. Melatonin, a pineal gland neurohormone, has been shown to participate in certain neuropsychopharmacological actions. The present study investigated the effect of melatonin on morphine-induced hyperalgesia and tolerance and possible involvement of protein kinase C (PKC)/N-methyl-D-aspartate (NMDA) pathway in melatonin-mediated. Methods Experiments were performed on adult, male Sprague–Dawley rats. Melatonin (10 mg/kg, intraperitoneal, i.p.) or saline was administrated 10 min after morphine injection (10 mg/kg, subcutaneous, s.c.) each day for consecutive 14 days. Withdrawal threshold of the hindpaw to mechanical and thermal stimulation was measured before any drug administration and one hour after melatonin or saline on each designated test day. On the 15th day, thermal withdrawal was measured after s.c. morphine (20 mg/kg), but not melatonin, and morphine tolerance was measured and expressed by MPAE% (percent of maximal possible anti-nociceptive effect) of morphine. Levels of expression of protein kinase C gamma (PKCγ) and NMDA receptor subtype NR1 in spinal cord were detected by Western blotting. Results The mechanical withdrawal threshold and thermal withdrawal latency decreased and shortened significantly (i.e., threshold decreased) in rats that received morphine treatment for two weeks compared with that in rats receiving saline. This morphine-induced mechanical and thermal hyperalgesia were greatly attenuated by co-administration of morphine with melatonin. The MPAE% representing morphine analgesic effect was reduced approximately 60% in rats that received morphine treatment. However, following the treatment of morphine with melatonin, the MPAE% was reduced only about 30%, comparing with those that received saline treatment as control. Administration of morphine alone resulted in significantly increased expression of PKCγ and NR1 proteins in the spinal cord. These increased levels of expression of PKCγ and NR1 were significantly inhibited by co-administration of morphine with melatonin. Conclusions Our findings demonstrate that melatonin have potential to attenuate repetitive morphine-induced hyperalgesia and tolerance, possibly by inhibiting PKCγ and NR1 activities in the spinal cord.
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Affiliation(s)
- Li Song
- Translational Medical Neuroscience Center, West China Hospital Sichuan University, Chengdu, Sichuan 610041 China ; Department of Anesthesiology, West China Hospital Sichuan University, Chengdu, Sichuan 610041 China
| | - Chaoran Wu
- Translational Medical Neuroscience Center, West China Hospital Sichuan University, Chengdu, Sichuan 610041 China ; Department of Anesthesiology, West China Hospital Sichuan University, Chengdu, Sichuan 610041 China
| | - Yunxia Zuo
- Translational Medical Neuroscience Center, West China Hospital Sichuan University, Chengdu, Sichuan 610041 China ; Department of Anesthesiology, West China Hospital Sichuan University, Chengdu, Sichuan 610041 China
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Kim E, Yoon SY, Shin YJ. Oxidative Stress in Cornea. OXIDATIVE STRESS IN APPLIED BASIC RESEARCH AND CLINICAL PRACTICE 2015. [DOI: 10.1007/978-1-4939-1935-2_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Abstract
Melatonin, a neurohormone synthesized by the epiphysis and extrapineal structures, has several functions including chronobiotic, antioxidant, oncostatic, immunomodulating, normothymic and anxiolytic ones. It impacts on the cardiovascular system and the gastrointestinal tract and is involved in reproductive functions, metabolism and body mass regulation. Moreover, recent studies have demonstrated the efficacy of melatonin in pain syndromes. The authors present a literature review on the studies of melatonin in treatment of fibromyalgia, headache, irritated bowel syndrome, chronic back pain and rheumatoid arthritis. Possible mechanisms of analgesic properties of melatonin are discussed. On one hand, there is the improvement of sleep and activation of own adaptive potential of melatonin by normalizing circadian rhythms inevitably disturbed in chronic pain syndromes. On the other hand, there are the data on the analgesic effect of melatonin realized through melatonin receptors and several neurotransmitter systems.
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Affiliation(s)
- Ju M Kurganova
- GBOU VPO 'Pervyj Moskovskij gosudarstvennyj meditsinskij universitet im. I.M. Sechenova', Moskva
| | - A B Danilov
- GBOU VPO 'Pervyj Moskovskij gosudarstvennyj meditsinskij universitet im. I.M. Sechenova', Moskva
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Laste G, Ripoll Rozisky J, Caumo W, Lucena da Silva Torres I. Short- but not long-term melatonin administration reduces central levels of brain-derived neurotrophic factor in rats with inflammatory pain. Neuroimmunomodulation 2015; 22:358-64. [PMID: 25871298 DOI: 10.1159/000380912] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 02/11/2015] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE To evaluate the effect of short- and long-term administration of melatonin on central brain-derived neurotrophic factor (BDNF) levels in rats with acute and chronic inflammatory pain. METHODS The animals were allocated to one of two experiments: experiment 1 or experiment 2. In experiment 1, all animals were injected with complete Freund's adjuvant (CFA) to induce inflammation and were randomly allocated to receiving melatonin (60 mg/kg) or vehicle. Injections were administered 1 h after CFA and once daily for 2 more days (for a total of 3 days of melatonin administration). In experiment 2, fifteen days after CFA injection, the animals were treated with melatonin (50 mg/kg) or vehicle for 8 days. The animals were killed by decapitation 24 h after the last melatonin or vehicle administration, and an ELISA assay was performed to detect BDNF expression in the spinal cord, brainstem, and prefrontal cortex of the rats in both groups. Data were analyzed using Student's t test and the results are expressed as means ± SEM. RESULTS In the first experiment, the BDNF levels of the melatonin group were reduced in the prefrontal cortex (Student's t test, p = 0.01) and increased in the spinal cord (Student's t test, p = 0.04). In experiment 2, BDNF levels were similar in both groups for all structures (Student's t test, p > 0.00 for all). A two-way ANOVA reveled a significant effect of structures (p = 0.0001) but not of treatment (p > 0.05). The prefrontal cortex presented higher BDNF levels than other structures (ANOVA/Student-Newman-Keuls test, p = 0.0001). Considering the relationship between BDNF levels in all three structures, we found an effect of central nervous system structures (p = 0.01) and an interaction between treatment and structures (p = 0.04). CONCLUSION The high spinal cord BDNF levels and the low prefrontal cortical BDNF levels observed in rats with acute CFA-induced inflammation following short-term melatonin administration may be related to the pain-modulating and neuroprotective effects of this protein. Long-term melatonin administration did not alter BDNF levels in chronic inflammation.
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Affiliation(s)
- Gabriela Laste
- Pain Pharmacology and Neuromodulation, Animal Models Laboratory, Pharmacology Department, Instituto de Cix00EA;ncias Bx00E1;sicas da Sax00FA;de, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
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Ullah HMA, Zaman S, Juhara F, Akter L, Tareq SM, Masum EH, Bhattacharjee R. Evaluation of antinociceptive, in-vivo & in-vitro anti-inflammatory activity of ethanolic extract of Curcuma zedoaria rhizome. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2014; 14:346. [PMID: 25242194 PMCID: PMC4190444 DOI: 10.1186/1472-6882-14-346] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 07/15/2014] [Indexed: 11/10/2022]
Abstract
BACKGROUND The present study was aimed to investigate the antinociceptive and anti-inflammatory activity of the Curcuma zedoaria (family Zingiberaceae) ethanolic rhizome extract in laboratory using both in vitro and in vivo methods so as to justify its traditional use in the above mentioned pathological conditions. METHODS Phytochemical screening was done to find the presence of various secondary metabolites of the plant. In vivo antinociceptive activity was performed employing the hot plate method, acidic acid induced writhing test and formalin induced writhing test on Swiss albino mice at doses of 250 and 500 mg/kg body weight. Anti-inflammatory activity test was done on Long Evans rats at two different doses (250 and 500 mg/kg body weight) by using carrageenan induced paw edema test. Finally in vitro anti-inflammatory test by protein-denaturation method was followed. Data were analyzed by one-way analysis of variance (ANOVA) and Dunnett's t-test was used as the test of significance. P value <0.05 was considered as the minimum level of significance. RESULTS Phytochemical screening revealed presence of tannins, saponins, flavonoids, gums & carbohydrates, steroids, alkaloids, reducing sugars and terpenoids in the extract. In the hot plate method, the extract increased the reaction time of heat sensation significantly to 61.99% and 78.22% at the doses of 250 and 500 mg/kg BW respectively. In acetic acid induced writhing test, the percent inhibition of writhing response by the extract was 48.28% and 54.02% at 250 and 500 mg/kg doses respectively (p < 0.001). The extract also significantly inhibited the licking response in both the early phase (64.49%, p < 0.01) and the late phase (62.37%, p < 0.01) in formalin induced writhing test. The extract significantly (p < 0.05, p < 0.01 and p < 0.001) inhibited carrageenan induced inflammatory response in rats in a dose related manner. In in-vitro anti-inflammatory test, the extract significantly inhibited protein denaturation of 77.15, 64.43, 53.04, 36.78 and 23.70% for doses of 500, 400, 300, 200 and 100 μg/mL respectively. CONCLUSIONS The results obtained from the tests indicate that the plant might have one or more secondary metabolite(s) having central and peripheral analgesic and anti-inflammatory activity.
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Affiliation(s)
- HM Arif Ullah
- />College of Pharmacy, Gyeongsang National University, 501 Jinju-daero, Jinju, Gyeongnam, 660-751 Republic of Korea
| | - Sayera Zaman
- />Department of Pharmaceutical Sciences, School of Life Sciences, North South University, Bashundhara, Dhaka, 1229 Bangladesh
| | - Fatematuj Juhara
- />Department of Pharmaceutical Sciences, School of Life Sciences, North South University, Bashundhara, Dhaka, 1229 Bangladesh
| | - Lucky Akter
- />Department of Pharmaceutical Sciences, School of Life Sciences, North South University, Bashundhara, Dhaka, 1229 Bangladesh
| | - Syed Mohammed Tareq
- />Department of Pharmacy, Faculty of Science and Engineering, Southern University Bangladesh, Chittagong, Bangladesh
| | - Emranul Haque Masum
- />Department of Pharmaceutical Sciences, School of Life Sciences, North South University, Bashundhara, Dhaka, 1229 Bangladesh
| | - Rajib Bhattacharjee
- />Department of Pharmaceutical Sciences, School of Life Sciences, North South University, Bashundhara, Dhaka, 1229 Bangladesh
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Huang F, He H, Fan W, Liu Y, Zhou H, Cheng B. Orofacial inflammatory pain affects the expression of MT1 and NADPH-d in rat caudal spinal trigeminal nucleus and trigeminal ganglion. Neural Regen Res 2014; 8:2991-3002. [PMID: 25206619 PMCID: PMC4146210 DOI: 10.3969/j.issn.1673-5374.2013.32.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Accepted: 09/11/2013] [Indexed: 12/26/2022] Open
Abstract
Very little is known about the role of melatonin in the trigeminal system, including the function of melatonin receptor 1. In the present study, adult rats were injected with formaldehyde into the right vibrissae pad to establish a model of orofacial inflammatory pain. The distribution of melatonin receptor 1 and nicotinamide adenine dinucleotide phosphate diaphorase in the caudal spinal trigeminal nucleus and trigeminal ganglion was determined with immunohistochemistry and histochemistry. The results show that there are significant differences in melatonin receptor 1 expression and nicotinamide adenine dinucleotide phosphate diaphorase expression in the trigeminal ganglia and caudal spinal nucleus during the early stage of orofacial inflammatory pain. Our findings suggest that when melatonin receptor 1 expression in the caudal spinal nucleus is significantly reduced, melatonin's regulatory effect on pain is attenuated.
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Affiliation(s)
- Fang Huang
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, Guangdong Province, China
| | - Hongwen He
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, Guangdong Province, China
| | - Wenguo Fan
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, Guangdong Province, China
| | - Yongliang Liu
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, Guangdong Province, China
| | - Hongyu Zhou
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, Guangdong Province, China
| | - Bin Cheng
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, Guangdong Province, China
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Mansour S, Djebli N, Ozkan EE, Mat A. In vivo antiinflammatory activity and chemical composition of Hypericum scabroides. ASIAN PAC J TROP MED 2014; 7S1:S514-20. [DOI: 10.1016/s1995-7645(14)60283-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 02/03/2014] [Accepted: 03/15/2014] [Indexed: 11/25/2022] Open
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Abstract
The perception of pain in children is easily influenced by environmental factors and psychological comorbidities that are known to play an important role in its origin and response to therapy. Chronic abdominal pain is one of the most commonly treated conditions in modern pediatric gastroenterology and is the hallmark of 'functional' disorders that include irritable bowel syndrome, functional dyspepsia, and functional abdominal pain. The development of pharmacological therapies for these disorders in adults and children has been limited by the lack of understanding of the putative, pathophysiological mechanisms that underlie them. Peripheral and central pain-signaling mechanisms are known to be involved in chronic pain originating from the gastrointestinal tract, but few therapies have been developed to target specific pathways or enhance correction of the underlying pathophysiology. The responses to therapy have been variable, potentially reflecting the heterogeneity of the disorders for which they are used. Only a few small, randomized clinical trials have evaluated the benefit of pain medications for chronic abdominal pain in children and thus, the decision on the most appropriate treatment is often based on adult studies and empirical data. This review discusses the most common, non-narcotic pharmacological treatments for chronic abdominal pain in children and includes a thorough review of the literature to support or refute their use. Because of the dearth of pediatric studies, the focus is on pharmacological and alternative therapies where there is sufficient evidence of benefit in either adults or children with chronic abdominal pain.
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Affiliation(s)
- Adrian Miranda
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI, 53226, USA,
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