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Khodabakhshi Korelaei A, Fallahi A, Hamblin MR, Ramezani F. The effect of melatonin administration on motor recovery after spinal cord injury in animal models: a systematic review and meta-analysis. Spinal Cord 2025; 63:135-148. [PMID: 39979444 DOI: 10.1038/s41393-025-01063-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 01/14/2025] [Accepted: 02/05/2025] [Indexed: 02/22/2025]
Abstract
STUDY DESIGN*: Systematic review and meta-analysis. OBJECTIVES In this study, the effects of the antioxidant melatonin on motor function after spinal cord injury were investigated in preclinical studies. SETTING IRAN METHODS: The search strategy was designed based on keywords related to melatonin and spinal cord injury. The primary screening was based on title and abstract, and the secondary screening was based on the full text of the articles. After extracting data from the articles, statistical analysis was performed using STATA software. Standardized mean differences were used to analyze the results of the included studies. Subgroup analysis and quality control of articles were also performed. RESULTS Based on the results of 29 separate experiments, melatonin showed a significant strong effect compared to the untreated group. The results showed that IP injection and multiple administrations days had the strong effect in the first three days as well as after 3-4 weeks. But more studies are needed to draw conclusions about its longer term effects. The analysis of MDA, SOD and GSH redox factors showed that the amount of MDA decreased and the amount of GSH increased in the treated animals. Also, the inflammatory factors IL-1Β and TNF-α as well as apoptosis and the rate of neuronal cell death, were reduced in animals that received melatonin, while the number of viable neurons was increased in melatonin treated animals. CONCLUSION Melatonin is an antioxidant supplement, which can be considered for clinical trials in human SCI patients. SPONSORSHIP IRAN University of medical sciences.
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Affiliation(s)
| | - Arash Fallahi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa
| | - Fatemeh Ramezani
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Meshkini A, Ohadi MAD, Mirghaderi P, Mirzaei F, Rafiei E, Allahyari N, Namvar M, Iranmehr A. Combined treatment with Minocycline and methylprednisolone in acute traumatic spinal cord Injury: A pilot study. INTERDISCIPLINARY NEUROSURGERY 2024; 36:101883. [DOI: 10.1016/j.inat.2023.101883] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2024] Open
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Xie L, Wu H, Huang X, Yu T. Melatonin, a natural antioxidant therapy in spinal cord injury. Front Cell Dev Biol 2023; 11:1218553. [PMID: 37691830 PMCID: PMC10485268 DOI: 10.3389/fcell.2023.1218553] [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: 05/07/2023] [Accepted: 08/11/2023] [Indexed: 09/12/2023] Open
Abstract
Spinal cord injury (SCI) is a sudden onset of disruption to the spinal neural tissue, leading to loss of motor control and sensory function of the body. Oxidative stress is considered a hallmark in SCI followed by a series of events, including inflammation and cellular apoptosis. Melatonin was originally discovered as a hormone produced by the pineal gland. The subcellular localization of melatonin has been identified in mitochondria, exhibiting specific onsite protection to excess mitochondrial reactive oxygen species and working as an antioxidant in diseases. The recent discovery regarding the molecular basis of ligand selectivity for melatonin receptors and the constant efforts on finding synthetic melatonin alternatives have drawn researchers' attention back to melatonin. This review outlines the application of melatonin in SCI, including 1) the relationship between the melatonin rhythm and SCI in clinic; 2) the neuroprotective role of melatonin in experimental traumatic and ischemia/reperfusion SCI, i.e., exhibiting anti-oxidative, anti-inflammatory, and anti-apoptosis effects, facilitating the integrity of the blood-spinal cord barrier, ameliorating edema, preventing neural death, reducing scar formation, and promoting axon regeneration and neuroplasticity; 3) protecting gut microbiota and peripheral organs; 4) synergizing with drugs, rehabilitation training, stem cell therapy, and biomedical material engineering; and 5) the potential side effects. This comprehensive review provides new insights on melatonin as a natural antioxidant therapy in facilitating rehabilitation in SCI.
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Affiliation(s)
- Lei Xie
- Institute of Sports Medicine and Health, Qingdao University, Qingdao, China
- Department of Orthopedic Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China
| | - Hang Wu
- Department of Orthopedic Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Xiaohong Huang
- Department of Orthopedic Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China
- Shandong Institute of Traumatic Orthopedics, Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tengbo Yu
- Institute of Sports Medicine and Health, Qingdao University, Qingdao, China
- Department of Orthopedic Surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China
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Bi J, Sun P, Feng E, Shen J, Chen C, Tan H, Li Z, Lin Y. Melatonin Synergizes With Methylprednisolone to Ameliorate Acute Spinal Cord Injury. Front Pharmacol 2022; 12:723913. [PMID: 35095480 PMCID: PMC8792471 DOI: 10.3389/fphar.2021.723913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/02/2021] [Indexed: 12/30/2022] Open
Abstract
Methylprednisolone (MP) is the drug of choice for treating spinal cord injury (SCI), but the aggressive dosage regimen used often results in adverse side effects. Therefore, MP should be combined with other drugs to lower the required dose. Melatonin is effective in alleviating nerve damage and inhibiting axonal degeneration. The combination of melatonin and half-dose methylprednisolone (HMP) for spinal cord injury treatment has never been reported. In this study, we established a rat model of T9 spinal cord injury by the Allen's method and assessed the synergistic therapeutic effects of melatonin and HMP by factorial design. Our results demonstrated that melatonin could synergize with HMP to ameliorate acute SCI through PI3K-AKT1 pathway. Combining melatonin with HMP significantly reduced the standard-dose of methylprednisolone and limited its adverse reactions, representing a promising option for treating acute SCI.
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Affiliation(s)
- Jiaqi Bi
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Emergency Department, SongBei Hospital of the Fourth Hospital Affiliated with Harbin Medical University, Harbin, China
- Postdoctoral Workstation, Harbin Children's Hospital, Harbin, China
| | - Peiyu Sun
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Orthopedics, Bejing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Erwei Feng
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianxiong Shen
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chong Chen
- Department of Spine Surgery, Orthopedics Center of Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Haining Tan
- Department of Orthopedic Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zheng Li
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Youxi Lin
- Department of Orthopedic Surgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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Charoenlux P, Utoomprurkporn N, Seresirikachorn K. The efficacy of corticosteroid after facial nerve neurorrhaphy: a systematic review and meta-analysis of randomized controlled trial. Braz J Otorhinolaryngol 2021; 89:79-89. [PMID: 34815200 PMCID: PMC9874359 DOI: 10.1016/j.bjorl.2021.09.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/26/2021] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVES The benefit of corticosteroids following facial nerve neurorrhaphy in the setting of complete transection is questionable. This systematic review and meta-analysis aimed to evaluate corticosteroid efficacy on facial nerve regeneration and functional recovery after complete disruption and neurorrhaphy. METHODS Randomized controlled trials on both human and animal models from Ovid MEDLINE and Ovid EMBASE studying corticosteroid efficacy in complete facial nerve disruption followed by neurorrhaphy were included. Data were extracted and pooled for meta-analysis. The outcomes were evaluated from electrophysiology, histology, and functional recovery. However, no randomized controlled trial in human was performed. Possibly, performing human trials with histopathology may not be feasible in clinical setting. RESULTS Six animal studies (248 participants) met inclusion criteria. Electrophysiologic outcomes revealed no differences in latency (Standardized Mean Difference (SMD) = -1.97, 95% CI -7.38 to 3.44, p = 0.47) and amplitude (SMD = 0.37, 95% CI -0.44 to 1.18, p = 0.37) between systemic corticosteroids and controls. When analysis compared topical corticosteroid and control, the results provided no differences in latency (Mean Difference (MD) = 0.10, 95% CI -0.04 to 0.24, p = 0.16) and amplitude (SMD = 0.01, 95% CI -0.08 to 0.10, p = 0.81). In histologic outcomes, the results showed no differences in axon diameter (MD = 0.13, 95% CI -0.15 to 0.41, p = 0.37) between systemic corticosteroid and control; however, the result in myelin thickness (MD = 0.06, 95% CI 0.04 to 0.08, p < 0.05) favored control group. When comparing systemic corticosteroid with control in eye blinking, the results favored control (MD = 1.33, 95% CI 0.60 to 2.06, p = 0.0004). CONCLUSIONS This evidence did not show potential benefits of systemic or topical corticosteroid deliveries after facial nerve neurorrhaphy in complete transection when evaluating electrophysiologic, histologic, and functional recovery outcomes in animal models.
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Affiliation(s)
- Prapitphan Charoenlux
- Department of Otolaryngology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Nattawan Utoomprurkporn
- Department of Otolaryngology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand,UCL Ear Institute, Faculty of Brain Science, University College London, London, United Kingdom
| | - Kachorn Seresirikachorn
- Department of Otolaryngology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand,Endoscopic Nasal and Sinus Surgery Excellence Center, King Chulalongkorn Memorial Hospital, Bangkok, Thailand,Corresponding author.
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Toraman M, Külekçi Öztürk S, Uslu Coşkun B, Güneş P. The effects of 4-aminopyridine and methylprednisolone on recovery of the facial nerve crush injury. Eur Arch Otorhinolaryngol 2020; 278:3057-3063. [PMID: 33226461 DOI: 10.1007/s00405-020-06483-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/09/2020] [Indexed: 11/28/2022]
Abstract
OBJECTIVE 4-Aminopyridine (4-AP) is a potassium channel blocker that enhances nerve excitability. In this study, rat models that have facial nerve crush injury (FNCI) were grouped and treated with methylprednisolone (MP), 4-AP, and a combination of these two drugs. Electrophysiologic and histopathologic outcomes of these groups will be compared with a control group. MATERIALS AND METHODS Thirty healthy male Wistar rats (mean weight of 265 g) were used in this study. The rats were randomly divided into five groups with six subjects in each: Group 1 (sham group), Group 2 (control group), Group 3 (MP group), Group 4 (4-aminopyridine group), and Group 5 (4-AP + MP group). All groups except the sham group underwent crush injury to the right facial nerve. Electrophysiologic and histologic recovery was recorded three weeks postoperatively. RESULTS The 4-AP group and the combined group had a more significant recovery at Nerve Excitability Thresholds (NET) at the end of three weeks. The methylprednisolone group and the control group had a minimal recovery of NET. Histologically, when compared with the control group, the combined group was the only group that had significant recovery at all three of axonal degeneration, axon diameter, and myelin thickness. CONCLUSION In this experimental study, we demonstrated that a combination treatment of 4-AP and MP is more effective in the recovery of peripheric FNCI than in the no-treatment control group and in the 4-AP- or MP-alone groups. Moreover, our results suggested that 4-AP can be a potent alternative to MP in the treatment of the FNCI. LEVEL OF EVIDENCE N/A.
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Affiliation(s)
- Murat Toraman
- Department of Otorhinolaryngology/Head and Neck Surgery, Tunceli State Hospital, Tunceli-Elazığ Street, Tunceli Devlet Hastanesi, 2th Florr, Tunceli, 62000, Turkey. .,Department of Otorhinolaryngology/Head and Neck Surgery, Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey.
| | - Semra Külekçi Öztürk
- Department of Otorhinolaryngology/Head and Neck Surgery, Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey
| | - Berna Uslu Coşkun
- Department of Otorhinolaryngology/Head and Neck Surgery, Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey.,Department of Otorhinolaryngology/Head and Neck Surgery, Şişli Hamidiye Etfal Education and Research Hospital, Istanbul, Turkey
| | - Pembegül Güneş
- Department of Pathology, Haydarpaşa Numune Education and Research Hospital, Istanbul, Turkey
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Whelan A, Halpine M, Christie SD, McVeigh SA. Systematic review of melatonin levels in individuals with complete cervical spinal cord injury. J Spinal Cord Med 2020; 43:565-578. [PMID: 30132738 PMCID: PMC7534275 DOI: 10.1080/10790268.2018.1505312] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Context: Pineal melatonin production is mediated by afferent signaling pathways that navigate through the cervicothoracic spinal cord. Melatonin profiles in individuals with complete cervical spinal cord injury (SCI) have not been systematically reviewed despite this proposed pathway. Objectives: The primary objective was to understand melatonin profiles in individuals with complete cervical SCI, as compared to healthy controls and those with thoracolumbar and incomplete cervical SCI. Secondary objectives were to understand the impact of injury chronicity and melatonin supplementation on melatonin values in adults with complete cervical SCI. Methods: This review (PROSPERO ID: CRD42017073767) searched several databases and gray literature sources from January 1978 to August 2017. Studies were eligible if they evaluated melatonin levels (blood, saliva or urinary metabolite measurements) in adults with complete cervical SCI. 390 studies were screened and 12 studies met final selection criteria. Given the heterogeneity in study designs, a narrative analysis was performed. Results: There is evidence that adults with complete cervical SCI have absent diurnal melatonin rhythms as compared to healthy controls and individuals with thoracolumbar SCI below T3. There is limited evidence comparing levels in individuals with incomplete tetraplegia. There is insufficient evidence describing profiles immediately (<2 weeks) after cervical SCI. Based on a limited number of studies, melatonin supplementation does not appear to improve sleep outcomes in adults with long-standing complete cervical SCI. Conclusions: Future research should explore melatonin levels acutely after cervical SCI and the impact of supplementation on non-sleep outcomes.
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Affiliation(s)
- Alexander Whelan
- Division of Physical Medicine and Rehabilitation, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Mary Halpine
- Division of Physical Medicine and Rehabilitation, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Sean D. Christie
- Department of Surgery (Neurosurgery), Dalhousie University, Halifax, Nova Scotia, Canada
| | - Sonja A. McVeigh
- Division of Physical Medicine and Rehabilitation, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
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Kleszczyński K, Slominski AT, Steinbrink K, Reiter RJ. Clinical Trials for Use of Melatonin to Fight against COVID-19 Are Urgently Needed. Nutrients 2020; 12:E2561. [PMID: 32847033 PMCID: PMC7551551 DOI: 10.3390/nu12092561] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/19/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023] Open
Abstract
The recent pandemic of COVID-19 has already infected millions of individuals and has resulted in the death of hundreds of thousands worldwide. Based on clinical features, pathology, and the pathogenesis of respiratory disorders induced by this and other highly homogenous coronaviruses, the evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response contribute to COVID-19 pathology; these are caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This leads to a cytokine storm and subsequent progression triggering acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), and often death. We and others have reported melatonin to be an anti-inflammatory and anti-oxidative molecule with a high safety profile. It is effective in critical care patients by reducing their vascular permeability and anxiety, inducing sedation, and improving their quality of sleep. As melatonin shows no harmful adverse effects in humans, it is imperative to introduce this indoleamine into clinical trials where it might be beneficial for better clinical outcomes as an adjuvant treatment of COVID-19-infected patients. Herein, we strongly encourage health care professionals to test the potential of melatonin for targeting the COVID-19 pandemic. This is urgent, since there is no reliable treatment for this devastating disease.
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Affiliation(s)
- Konrad Kleszczyński
- Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany;
| | - Andrzej T. Slominski
- Department of Dermatology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA;
- Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL 35294, USA
| | - Kerstin Steinbrink
- Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany;
| | - Russel J. Reiter
- Department of Cellular and Structural Biology, UT Health, San Antonio, TX 78229, USA;
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Hale C, Yonan J, Batarseh R, Chaar R, Jonak CR, Ge S, Binder D, Rodgers VGJ. Implantable Osmotic Transport Device Can Reduce Edema After Severe Contusion Spinal Cord Injury. Front Bioeng Biotechnol 2020; 8:806. [PMID: 32754586 PMCID: PMC7366393 DOI: 10.3389/fbioe.2020.00806] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 06/23/2020] [Indexed: 12/30/2022] Open
Abstract
Recent findings from the ISCoPe study indicate that, after severe contusion to the spinal cord, edema originating in the spinal cord accumulates and compresses the tissue against the surrounding dura mater, despite decompressive laminectomy. It is hypothesized that this compression results in restricted flow of cerebrospinal fluid (CSF) in the subarachnoid space and central canal and ultimately collapses local vasculature, exacerbating ischemia and secondary injury. Here we developed a surgically mounted osmotic transport device (OTD) that rests on the dura and can osmotically remove excess fluid at the injury site. Tests were performed in 4-h studies immediately following severe (250 kD) contusion at T8 in rats using the OTD. A 3-h treatment with the OTD after 1-h post injury significantly reduced spinal cord edema compared to injured controls. A first approximation mathematical interpretation implies that this modest reduction in edema may be significant enough to relieve compression of local vasculature and restore flow of CSF in the region. In addition, we determined the progression of edema up to 28 days after insult in the rat for the same injury model. Results showed peak edema at 72 h. These preliminary results suggest that incorporating the OTD to operate continuously at the site of injury throughout the critical period of edema progression, the device may significantly improve recovery following contusion spinal cord injury.
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Affiliation(s)
- Christopher Hale
- Department of Bioengineering, University of California, Riverside, Riverside, CA, United States
| | - Jennifer Yonan
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Ramsey Batarseh
- Department of Bioengineering, University of California, Riverside, Riverside, CA, United States
| | - Roman Chaar
- Department of Bioengineering, University of California, Riverside, Riverside, CA, United States
| | - Carrie R Jonak
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Shaokui Ge
- Division of Biostatistics & Bioinformatics, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Devin Binder
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
| | - Victor G J Rodgers
- Department of Bioengineering, University of California, Riverside, Riverside, CA, United States
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Shneider A, Kudriavtsev A, Vakhrusheva A. Can melatonin reduce the severity of COVID-19 pandemic? Int Rev Immunol 2020; 39:153-162. [PMID: 32347747 DOI: 10.1080/08830185.2020.1756284] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The current COVID-19 pandemic is one of the most devastating events in recent history. The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children don't suffer from COVID-19 as much as their grandparents and have a much higher melatonin level. Bats are nocturnal animals possessing high levels of melatonin, which may contribute to their high anti-viral resistance. Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms, and/or reduce the immuno-pathology of coronavirus infection on patients' health after the active phase of the infection is over.
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Affiliation(s)
- Alex Shneider
- CureLab Oncology, Inc, Dedham, Massachusetts, USA.,Department of Molecular Biology, Ariel University, Ariel, Israel
| | - Aleksandr Kudriavtsev
- Biological Faculty, Lomonosov Moscow State University, Moscow, Russia.,Emanuel Institute of Biochemical Phisics, RAS, Moscow, Russia
| | - Anna Vakhrusheva
- Biological Faculty, Lomonosov Moscow State University, Moscow, Russia
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de Barros AGC, Cristante AF, dos Santos GB, Natalino RJM, Ferreira RJR, de Barros-Filho TEP. Evaluation of the effects of erythropoietin and interleukin-6 in rats submitted to acute spinal cord injury. Clinics (Sao Paulo) 2019; 74:e674. [PMID: 31433044 PMCID: PMC6691840 DOI: 10.6061/clinics/2019/e674] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 03/19/2019] [Indexed: 12/02/2022] Open
Abstract
OBJECTIVE To evaluate the effects of interleukin-6 (IL-6) and erythropoietin (EPO) in experimental acute spinal cord injury (SCI) in rats. METHODS Using standardized equipment, namely, a New York University (NYU) Impactor, a SCI was produced in 50 Wistar rats using a 10-g weight drop from a 12.5-mm height. The rats were divided into the following 5 groups of 10 animals each: "Group EPO", treated with erythropoietin only; "Group EPO + IL-6", treated with both substances; "Group IL-6", receiving IL-6 administration only; "Group Placebo", receiving a placebo solution; and "Group Sham", submitted to an incomplete procedure (only laminectomy, without SCI). All drugs and the placebo solution were administered intraperitoneally for three weeks. The animals were followed up for 42 days. Functional motor recovery was monitored by the Basso, Beattie, and Bresnahan (BBB) scale on days 2, 7, 14, 21, 28, 35 and 42. Motor-evoked potential tests were performed on the 42nd day. Histological analysis was performed after euthanasia. RESULTS The group receiving EPO exhibited superior functional motor results on the BBB scale. IL-6 administration alone was not superior to the placebo treatment, and the IL-6 combination with EPO yielded worse results than did EPO alone. CONCLUSIONS Using EPO after acute SCI in rats yielded benefits in functional recovery. The combination of EPO and IL-6 showed benefits, but with inferior results compared to those of isolated EPO; moreover, isolated use of IL-6 resulted in no benefit.
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Affiliation(s)
| | - Alexandre Fogaça Cristante
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
- Corresponding author. E-mail:
| | - Gustavo Bispo dos Santos
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Renato José Mendonça Natalino
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Ricardo José Rodriguez Ferreira
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
| | - Tarcísio Eloy Pessoa de Barros-Filho
- Instituto de Ortopedia e Traumatologia (IOT), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR
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12
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Tuna Edizer D, Dönmez Z, Gül M, Yiğit Ö, Yiğitcan B, Adatepe T, Uzun N. Effects of Melatonin and Dexamethasone on Facial Nerve Neurorrhaphy. J Int Adv Otol 2018; 15:43-50. [PMID: 30541731 DOI: 10.5152/iao.2018.3273] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVES To investigate the effects of topical and systemic administrations of melatonin and dexamethasone on facial nerve regeneration. MATERIALS AND METHODS In total, 50 male albino Wistar rats underwent facial nerve axotomy and neurorrhaphy. The animals were divided into 5 groups: control, topical melatonin, systemic melatonin, topical dexamethasone, and systemic dexamethasone. Nerve conduction studies were performed preoperatively and at 3, 6, 9, and 12 weeks after drug administrations. Amplitude and latency of the compound muscle action potentials were recorded. Coapted facial nerves were investigated under light and electron microscopy. Nerve diameter, axon diameter, and myelin thickness were recorded quantitatively. RESULTS Amplitudes decreased and latencies increased in both the melatonin and dexamethasone groups. At the final examination, the electrophysiological evidence of facial nerve degeneration was not significantly different between the groups. Histopathological examinations revealed the largest nerve diameter in the melatonin groups, followed by the dexamethasone and control groups (p<0.05). Axon diameter of the control group was smaller than those of the melatonin (topical and systemic) and topical dexamethasone groups (p<0.05). The melatonin groups had almost normal myelin ultrastructure. CONCLUSION Electrophysiological evaluation did not reveal any potential benefit of dexamethasone and melatonin in contrast to histopathological examination, which revealed beneficial effects of melatonin in particular. These agents may increase the regeneration of facial nerves, but electrophysiological evidence of regeneration may appear later.
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Affiliation(s)
- Deniz Tuna Edizer
- Department of Otorhinolaryngology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Zehra Dönmez
- Department of Otorhinolaryngology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Mehmet Gül
- Department of Histology and Embryology, İnönü University School of Medicine, Malatya, Turkey
| | - Özgür Yiğit
- Department of Otorhinolaryngology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Birgül Yiğitcan
- Department of Histology and Embryology, İnönü University School of Medicine, Malatya, Turkey
| | - Turgut Adatepe
- Department of Electrophysiology, İstanbul Training and Research Hospital, İstanbul, Turkey
| | - Nurten Uzun
- Department of Neurology, İstanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, İstanbul, Turkey
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Zhang Y, Zhang WX, Zhang YJ, Liu YD, Liu ZJ, Wu QC, Guan Y, Chen XM. Melatonin for the treatment of spinal cord injury. Neural Regen Res 2018; 13:1685-1692. [PMID: 30136678 PMCID: PMC6128058 DOI: 10.4103/1673-5374.238603] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Spinal cord injury (SCI) from trauma or disease severely impairs sensory and motor function. Neurorehabilitation after SCI is a complex medical process that focuses on improving neurologic function and repairing damaged connections in the central nervous system. An increasing number of preclinical studies suggest that melatonin may be useful for the treatment of SCI. Melatonin is an indolamine that is primarily secreted by the pineal gland and known to be regulated by photoperiodicity. However, it is also a versatile hormone with antioxidative, antiapoptotic, neuroprotective, and anti-inflammatory properties. Here, we review the neuroprotective properties of melatonin and the potential mechanisms by which it might be beneficial in the treatment of SCI. We also describe therapies that combine melatonin with exercise, oxytetracycline, and dexamethasone to attenuate the secondary injury after SCI and limit potential side effects. Finally, we discuss how injury at different spinal levels may differentially affect the secretion of melatonin.
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Affiliation(s)
- Yan Zhang
- Central Laboratory, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Wen-Xiu Zhang
- Central Laboratory, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Yan-Jun Zhang
- Department of Orthopedics, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Ya-Dong Liu
- Department of Orthopedics, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Zong-Jian Liu
- Central Laboratory, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Qi-Chao Wu
- Department of Orthopedics, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Yun Guan
- Central Laboratory, Beijing Luhe Hospital, Capital Medical University, Beijing, China; Department of Anesthesiology and Critical Care Medicine; Department of Neurological Surgery, Johns Hopkins University, Baltimore, MD, USA
| | - Xue-Ming Chen
- Central Laboratory; Department of Orthopedics, Beijing Luhe Hospital, Capital Medical University, Beijing, China
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14
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Ye Y, Feng TT, Peng YR, Hu SQ, Xu T. The treatment of spinal cord injury in rats using bone marrow-derived neural-like cells induced by cerebrospinal fluid. Neurosci Lett 2017; 666:85-91. [PMID: 29274438 DOI: 10.1016/j.neulet.2017.12.043] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 12/15/2017] [Accepted: 12/19/2017] [Indexed: 12/13/2022]
Abstract
This study aimed to evaluate the effect of bone mesenchymal stem cells (BMSCs) and BMSC neural-like cells (BMSC-Ns) on the spinal cord injury (SCI) in the rat model of SCI. BMSC-Ns were prepared from the third passage of BMSCs by induction of healthy cerebrospinal fluid (CSF) of an adult human. The SCI rat model was established through a surgical procedure, and after 7 days the rats were randomly divided into 3 (A, B and C) groups. Groups A (BMSC-Ns) and B (BMSCs) were treated with 1 × 106/20 μl cells, while group C (saline) was treated with saline, all via intracerebroventricular injection. After transplantation, the BBB score of group A was significantly higher than that of group B, which in turn was significantly higher than that of group C (P < .05). The levels of Bdnf, Ngf, Ntf3 were statistically significantly higher in group A than those in groups B and C (P < .05). The levels of 5-HT, NA, Ach, DA, GABA in group A were significantly higher than those in groups B and C, whereas the level of Glu was significantly lower in group A than that in groups B and C (P < .05). The histopathological data showed remarkably less necrosis of the spinal cord in group A, compared to that in groups B and C. Transplanting BMSC-Ns or BMSCs into the lateral ventricles improved the neurological function of rats with SCI. Moreover, BMSC-Ns were significantly more effective than BMSCs, which provides a possible approach for the treatment of SCI.
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Affiliation(s)
- Ying Ye
- Institute of Emergency Rescue Medicine & Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Emergency Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Ting-Ting Feng
- Emergency Center, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, 222000, China
| | - Yi-Ran Peng
- Department of Clinical Medicine, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Shu-Qun Hu
- Institute of Emergency Rescue Medicine & Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China
| | - Tie Xu
- Institute of Emergency Rescue Medicine & Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu 221002, China; Emergency Center, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221002, China.
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15
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Najafi M, Shirazi A, Motevaseli E, Rezaeyan AH, Salajegheh A, Rezapoor S. Melatonin as an anti-inflammatory agent in radiotherapy. Inflammopharmacology 2017; 25:403-413. [DOI: 10.1007/s10787-017-0332-5] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 02/19/2017] [Indexed: 02/07/2023]
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KOFF MARCOANTONIOEDUARDO, AJIBOYE LUKMANOLALEKAN, LISBOA NATÁLIADIEL, FALAVIGNA ASDRUBAL. SYSTEMATIC REVIEW OF RECOVERY OF SPINAL CORD INJURY WITH ANTIOXIDANT THERAPY. COLUNA/COLUMNA 2017. [DOI: 10.1590/s1808-1851201716011171639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
ABSTRACT The objective of the paper is to analyze the frequency and efficacy of experimental studies with antioxidant therapy. A search was conducted in the pubmed.gov database using the keywords "antioxidants" AND "spinal cord injury", from January 2000 to December 2015, resulting in 686 articles. Studies of non-traumatic injuries, non-antioxidant therapies, absence of neurological and functional evaluation, and non-experimental studies were excluded, leaving a total of 43 articles. The most used therapies were melatonin (16.2%), quercetin (9.3%), epigallocatechin and edaravone (6.9%). The most frequent route of administration was intraperitoneal (72.09%). The dose and mode of administration varied greatly, with a single dose being the most commonly used (39.53%). The time elapsed from trauma to treatment was 0-15 minutes (41.8%), 15-60 minutes (30%) and over 60 minutes (10.6%). Histological analysis was performed in 32 studies (74.41%). The BBB scale was the main functional measure applied (55.8%), followed by the inclined plane test (16.2%) and the Tarlov scale (13.9%). Positive outcomes were observed in 37 studies (86.04%). The heterogeneity of antioxidant therapy, with different types, doses, and measurements observed, limits the comparison of efficacy. Standardized protocols are required to make clinical translation possible.
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17
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Yonan JM, Binder DK. Aquaporin-4 and spinal cord injury. World J Neurol 2016; 6:1-13. [DOI: 10.5316/wjn.v6.i1.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 12/25/2015] [Accepted: 01/19/2016] [Indexed: 02/06/2023] Open
Abstract
Edema formation is a major problem following traumatic spinal cord injury (SCI) that acts to exacerbate secondary damage. Severity of edema correlates with reduced neurological outcome in human patients. To date, there are no effective treatments to directly resolve edema within the spinal cord. The aquaporin-4 (AQP4) water channel is found on membranes of astrocytic endfeet in direct contact with blood vessels, the glia limitans in contact with the cerebrospinal fluid and ependyma around the central canal. Being so locally expressed at the interface between fluid and tissue allow AQP4 channels to play an important role in the bidirectional regulation of water homeostasis under normal conditions and following trauma. With the need to better understand the pathophysiology underlying the devastating cellular events in SCI, animal models have become an integral part of exploration. Inevitably, several injury models have been developed (contusion, compression, transection) resulting in difficult interpretation between studies with conflicting results. This is true in the case of understanding the role of AQP4 in the progression and resolution of edema following SCI, whose role is still not completely understood and is highly dependent on the type of edema present (vasogenic vs cytotoxic). Here, we discuss regulation of AQP4 in varying injury models and the effects of potential therapeutic interventions on expression, edema formation and functional recovery. Better understanding of the precise role of AQP4 following a wide range of injuries will help to understand optimal treatment timing following human SCI for prime therapeutic benefit and enhanced neurological outcome.
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18
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Yang L, Yao M, Lan Y, Mo W, Sun YL, Wang J, Wang YJ, Cui XJ. Melatonin for Spinal Cord Injury in Animal Models: A Systematic Review and Network Meta-Analysis. J Neurotrauma 2016; 33:290-300. [PMID: 26414869 DOI: 10.1089/neu.2015.4038] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Long Yang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Min Yao
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yun Lan
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Mo
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue-li Sun
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yong-jun Wang
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xue-jun Cui
- Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Institute of Spine Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Decreased GFAP expression and improved functional recovery in contused spinal cord of rats following valproic acid therapy. Neurochem Res 2014; 39:2319-33. [PMID: 25205382 DOI: 10.1007/s11064-014-1429-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 08/20/2014] [Accepted: 09/02/2014] [Indexed: 12/13/2022]
Abstract
Many studies have illustrated that much of the post-traumatic degeneration of the spinal cord cells is caused by the secondary mechanism. The aim of this study is to evaluate the effect of the anti-inflammatory property of valproic acid (VPA) on injured spinal cords (SC). The rats with the contused SC received intraperitoneal single injection of VPA (150, 200, 300, 400 or 500 mg/kg) at 2, 6, 12 and 24 h post-injury. Basso-Beattie-Bresnahan (BBB) test and H-reflex evaluated the functional outcome for 12 weeks. The SC were investigated 3 months post-injury using morphometry and glial fibrillary acid protein (GFAP) expression. Reduction in cavitation, H/M ratio, BBB scores and GFAP expression in the treatment groups were significantly more than that of the untreated one (P < 0.05). The optimal improvement in the condition of the contused rats was in the ones treated at the acute phase of injury with 300 mg/kg of VPA at 12 h post-injury, they had the highest increase in BBB score and decrease in astrogliosis and axonal loss. We conclude that treating the contused rats with 300 mg/kg of VPA at 12 h post-injury improves the functional outcome and reduces the traumatized SC gliosis.
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20
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Demir F, Güzel A, Kat C, Karadeniz C, Akdemir U, Okuyucu A, Gacar A, Özdemir S, Güvenç T. A combination of methylprednisolone and quercetin is effective for the treatment of cardiac contusion following blunt chest trauma in rats. Braz J Med Biol Res 2014; 47:766-72. [PMID: 25098616 PMCID: PMC4143204 DOI: 10.1590/1414-431x20144021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2014] [Accepted: 05/22/2014] [Indexed: 11/25/2022] Open
Abstract
Cardiac contusion is a potentially fatal complication of blunt chest trauma. The
effects of a combination of quercetin and methylprednisolone against trauma-induced
cardiac contusion were studied. Thirty-five female Sprague-Dawley rats were divided
into five groups (n=7) as follows: sham, cardiac contusion with no therapy, treated
with methylprednisolone (30 mg/kg on the first day, and 3 mg/kg on the following
days), treated with quercetin (50 mg·kg−1·day−1), and treated
with a combination of methylprednisolone and quercetin. Serum troponin I (Tn-I) and
tumor necrosis factor-alpha (TNF-α) levels and cardiac histopathological findings
were evaluated. Tn-I and TNF-α levels were elevated after contusion (P=0.001 and
P=0.001). Seven days later, Tn-I and TNF-α levels decreased in the rats treated with
methylprednisolone, quercetin, and the combination of methylprednisolone and
quercetin compared to the rats without therapy, but a statistical significance was
found only with the combination therapy (P=0.001 and P=0.011, respectively).
Histopathological degeneration and necrosis scores were statistically lower in the
methylprednisolone and quercetin combination group compared to the group treated only
with methylprednisolone (P=0.017 and P=0.007, respectively). However, only
degeneration scores were lower in the combination therapy group compared to the group
treated only with quercetin (P=0.017). Inducible nitric oxide synthase positivity
scores were decreased in all treatment groups compared to the untreated groups
(P=0.097, P=0.026, and P=0.004, respectively). We conclude that a combination of
quercetin and methylprednisolone can be used for the specific treatment of cardiac
contusion.
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Affiliation(s)
- F Demir
- Department of Pediatric Cardiology, Faculty of Medicine, Dicle University, Diyarbak?r, Turkey
| | - A Güzel
- Department of Pediatrics, Faculty of Medicine, Ondokuz May?s University, Samsun, Turkey
| | - C Kat
- Department of Emergency Medicine, Faculty of Medicine, Ondokuz May?s University, Samsun, Turkey
| | - C Karadeniz
- Pediatric Cardiology Services, Behçet Uz Children's Hospital, ?zmir, Turkey
| | - U Akdemir
- Department of Emergency Medicine, Faculty of Medicine, Ondokuz May?s University, Samsun, Turkey
| | - A Okuyucu
- Department of Medical Biochemistry, Faculty of Medicine, Ondokuz May?s University, Samsun, Turkey
| | - A Gacar
- Department of Pathology, Faculty of Veterinary Medicine, Ondokuz May?s University, Samsun, Turkey
| | - S Özdemir
- Department of Pediatrics, Faculty of Medicine, Ondokuz May?s University, Samsun, Turkey
| | - T Güvenç
- Department of Pathology, Faculty of Veterinary Medicine, Ondokuz May?s University, Samsun, Turkey
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21
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Evaluation of the neuroprotective effect of chrysin via modulation of endogenous biomarkers in a rat model of spinal cord injury. J Nat Med 2014; 68:586-603. [DOI: 10.1007/s11418-014-0840-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 04/08/2014] [Indexed: 01/14/2023]
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Akdemir HU, Güzel A, Katı C, Duran L, Alaçam H, Gacar A, Güvenç T, Murat N, Sişman B. The evaluation of different treatment protocols for trauma-induced lung injury in rats. J Thorac Dis 2014; 6:66-73. [PMID: 24605218 DOI: 10.3978/j.issn.2072-1439.2013.12.54] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 12/30/2013] [Indexed: 11/14/2022]
Abstract
BACKGROUND Lung contusion is an important factor that affects mortality and morbidity of lung injury after blunt chest trauma (BCT). The present study aims to evaluate the effectiveness of different treatment regimens on BCT-induced lung injury. METHODS A total of 35 Sprague Dawley rats were divided into five experimental groups (n=7): sham, control; BCT; BCT + MP, BCT group treated with methylprednisolone (MP; 30 mg/kg on first day and 3 mg/kg/d on the following days); BCT + Q, BCT group treated with quercetin (Q; 50 mg/kg/d for seven days); and BCT + MP + Q, BCT group treated with the same doses of MP and Q. Serum Clara Cell Protein-16 (CC-16), thiobarbituric acid reactive substances (TBARS), and superoxide dismutase (SOD) levels were analyzed to determine histopathological changes in the lung tissues. RESULTS Elevated serum CC-16 and TBARS levels and reduced serum SOD levels were found in the BCT group compared to the Sham group. There was a significant change in the serum CC-16 levels in the BCT + MP group compared to the Sham group. Serum TBARS levels were significantly lower in the BCT + MP and BCT + Q group compared to the BCT group. The combined therapy regimen yielded significantly decreased CC-16 levels and increased serum SOD levels compared to the individual treatment groups. Serum TBARS levels did not significantly differ between the BCT + MP + Q group and the other treatment groups. Compared to the BCT + MP + Q group, the BCT + MP group showed significantly lower alveolar edema (AED) and alveolar exudate (AEX) scores, while the BCT + Q group showed significantly lower peribronchial inflammatory cell infiltration (PICI) and AED scores. CONCLUSIONS The combined usage of quercetin and low dose MP treatment after initial high dose MP at the early stage of lung injury after BCT is more effective.
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Affiliation(s)
- Hızır Ufuk Akdemir
- 1 Faculty of Medicine, Department of Emergency Medicine, 2 Faculty of Medicine, Department of Chest Diseases, 3 Faculty of Medicine, Department of Medical Biochemistry, 4 Faculty of Veterinary Medicine, Department of Pathology, 5 Department of Industrial Engineering, Ondokuz Mayıs University, Samsun, Turkey
| | - Aygül Güzel
- 1 Faculty of Medicine, Department of Emergency Medicine, 2 Faculty of Medicine, Department of Chest Diseases, 3 Faculty of Medicine, Department of Medical Biochemistry, 4 Faculty of Veterinary Medicine, Department of Pathology, 5 Department of Industrial Engineering, Ondokuz Mayıs University, Samsun, Turkey
| | - Celal Katı
- 1 Faculty of Medicine, Department of Emergency Medicine, 2 Faculty of Medicine, Department of Chest Diseases, 3 Faculty of Medicine, Department of Medical Biochemistry, 4 Faculty of Veterinary Medicine, Department of Pathology, 5 Department of Industrial Engineering, Ondokuz Mayıs University, Samsun, Turkey
| | - Latif Duran
- 1 Faculty of Medicine, Department of Emergency Medicine, 2 Faculty of Medicine, Department of Chest Diseases, 3 Faculty of Medicine, Department of Medical Biochemistry, 4 Faculty of Veterinary Medicine, Department of Pathology, 5 Department of Industrial Engineering, Ondokuz Mayıs University, Samsun, Turkey
| | - Hasan Alaçam
- 1 Faculty of Medicine, Department of Emergency Medicine, 2 Faculty of Medicine, Department of Chest Diseases, 3 Faculty of Medicine, Department of Medical Biochemistry, 4 Faculty of Veterinary Medicine, Department of Pathology, 5 Department of Industrial Engineering, Ondokuz Mayıs University, Samsun, Turkey
| | - Ayhan Gacar
- 1 Faculty of Medicine, Department of Emergency Medicine, 2 Faculty of Medicine, Department of Chest Diseases, 3 Faculty of Medicine, Department of Medical Biochemistry, 4 Faculty of Veterinary Medicine, Department of Pathology, 5 Department of Industrial Engineering, Ondokuz Mayıs University, Samsun, Turkey
| | - Tolga Güvenç
- 1 Faculty of Medicine, Department of Emergency Medicine, 2 Faculty of Medicine, Department of Chest Diseases, 3 Faculty of Medicine, Department of Medical Biochemistry, 4 Faculty of Veterinary Medicine, Department of Pathology, 5 Department of Industrial Engineering, Ondokuz Mayıs University, Samsun, Turkey
| | - Naci Murat
- 1 Faculty of Medicine, Department of Emergency Medicine, 2 Faculty of Medicine, Department of Chest Diseases, 3 Faculty of Medicine, Department of Medical Biochemistry, 4 Faculty of Veterinary Medicine, Department of Pathology, 5 Department of Industrial Engineering, Ondokuz Mayıs University, Samsun, Turkey
| | - Bülent Sişman
- 1 Faculty of Medicine, Department of Emergency Medicine, 2 Faculty of Medicine, Department of Chest Diseases, 3 Faculty of Medicine, Department of Medical Biochemistry, 4 Faculty of Veterinary Medicine, Department of Pathology, 5 Department of Industrial Engineering, Ondokuz Mayıs University, Samsun, Turkey
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Toros SZ, Karaca ÇT, Güneş P, Oysu Ç, Ertugay ÇK, Naiboğlu B, Elbüken E, Egeli E. Hyperbaric oxygen versus steroid in facial nerve injury: an experimental animal study. Am J Otolaryngol 2013; 34:530-6. [PMID: 23890702 DOI: 10.1016/j.amjoto.2013.06.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 06/18/2013] [Accepted: 06/21/2013] [Indexed: 10/26/2022]
Abstract
OBJECTIVE The aim of this experimental study was to evaluate the effects of hyperbaric oxygen, methylprednisolone and combined hyperbaric oxygen-methylprednisolone treatments on traumatic facial nerve regeneration in rats. SUBJECTS AND METHODS After exposure to facial nerve injury, four groups of rats were created with five subjects in each group: Group 1 (hyperbaric oxygen), group 2 (control), group 3 (combined hyperbaric oxygen-methylprednisolone), group 4 (methylprednisolone). Facial nerve specimens from sacrificed animals were examined for axonal degeneration, vascular congestion, macro vacuolization, axon diameter and thickness of myelin sheath. RESULTS There were significant differences with regard to axonal degeneration, vascular congestion and axon diameter between group 3 and the control group. In addition to lower axonal degeneration and vascular congestion, a larger diameter of axons was observed in group 3. There were significant differences with regard to vascular congestion and axon diameter between group 4 and the control group. We observed thicker myelin and lower axonal degeneration in group 3 compared with group 4. CONCLUSION The combination therapy with hyperbaric oxygen and methylprednisolone had an additive beneficial effect on regeneration of the facial nerve and may provide better treatment outcomes than methylprednisolone or hyperbaric oxygen therapy alone.
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Fu Z, Lu H, Jiang J, Jiang H, Zhang Z. Methylprednisolone inhibits Nogo-A protein expression after acute spinal cord injury. Neural Regen Res 2013; 8:404-9. [PMID: 25206681 PMCID: PMC4146133 DOI: 10.3969/j.issn.1673-5374.2013.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 10/29/2012] [Indexed: 11/18/2022] Open
Abstract
Oligodendrocyte-produced Nogo-A has been shown to inhibit axonal regeneration. Methylprednisolone plays an effective role in treating spinal cord injury, but the effect of methylprednisolone on Nogo-A in the injured spinal cord remains unknown. The present study established a rat model of acute spinal cord injury by the weight-drop method. Results showed that after injury, the motor behavior ability of rats was reduced and necrotic injury appeared in spinal cord tissues, which was accompanied by increased Nogo-A expression in these tissues. After intravenous injection of high-dose methylprednisolone, although the pathology of spinal cord tissue remained unchanged, Nogo-A expression was reduced, but the level was still higher than normal. These findings implicate that methylprednisolone could inhibit Nogo-A expression, which could be a mechanism by which early high dose methylprednisolone infusion helps preserve spinal cord function after spinal cord injury.
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Affiliation(s)
- Zhaozong Fu
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hai Lu
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Jianming Jiang
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Hui Jiang
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Zhaofei Zhang
- Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Song Y, Zeng Z, Jin C, Zhang J, Ding B, Zhang F. Protective effect of ginkgolide B against acute spinal cord injury in rats and its correlation with the Jak/STAT signaling pathway. Neurochem Res 2012; 38:610-9. [PMID: 23274522 DOI: 10.1007/s11064-012-0959-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 11/20/2012] [Accepted: 12/19/2012] [Indexed: 11/25/2022]
Abstract
This study aimed to investigate the correlation between ginkgolide B (GB) and the JAK/STAT signaling pathway and to explore its regulating effect on secondary cell apoptosis following spinal cord injury (SCI), to elucidate the protective mechanism GB against acute SCI. Sprague-Dawley rats were randomly divided into a sham-operated group, an SCI group, an SCI + GB group, an SCI + methylprednisolone (MP) group, and an SCI + specific JAK inhibitor AG490 group. A rat model of acute SCI was established using the modified Allen's method. At 4 h, 12 h, 1 day, 3 days, 7 days and 14 days after injury, injured T10 spinal cord specimens were harvested. GB significantly increased inclined plane test scores and Basso, Beattie, and Bresnahan scale scores in SCI rats from postoperative day 3 to day 14. The effect was equal to that of the positive control drug, MP. Western blot analysis showed that JAK(2) was significantly phosphorylated from 4 h after SCI, peaked at 12 h and gradually decreased thereafter, accompanied by phosphorylation of STAT(3) with a similar time course. GB was shown to significantly inhibit the phosphorylation of JAK(2) and STAT(3) in rats with SCI. It significantly increased the ratio of B cell CLL/lymphoma-2 (Bcl-2)/Bcl-2-associated X protein (Bax) protein expression at 24 h, led to an obvious down-regulation of caspase-3 gene and protein expression at 3 days, and significantly decreased the cell apoptosis index at each time point after SCI. This effect was similar to that obtained with the JAK-specific inhibitor, AG490. Our experimental findings indicated that GB can protect rats against acute SCI, and that its underlying mechanism may be related to the inhibition of JAK/STAT signaling pathway activation, improvement of the Bcl-2/Bax ratio, decreased caspase-3 gene and protein expression and further inhibition of secondary cell apoptosis following SCI.
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Affiliation(s)
- Yongxing Song
- Department of Orthopaedics, Hospital of Zhejiang General Corps of Armed Police Forces, Jiaxing, 314000, Zhejiang Province, People's Republic of China
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Priestley JV, Michael-Titus AT, Tetzlaff W. Limiting spinal cord injury by pharmacological intervention. HANDBOOK OF CLINICAL NEUROLOGY 2012; 109:463-484. [PMID: 23098731 DOI: 10.1016/b978-0-444-52137-8.00029-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The direct primary mechanical trauma to neurons, glia and blood vessels that occurs with spinal cord injury (SCI) is followed by a complex cascade of biochemical and cellular changes which serve to increase the size of the injury site and the extent of cellular and axonal loss. The aim of neuroprotective strategies in SCI is to limit the extent of this secondary cell loss by inhibiting key components of the evolving injury cascade. In this review we will briefly outline the pathophysiological events that occur in SCI, and then review the wide range of neuroprotective agents that have been evaluated in preclinical SCI models. Agents will be considered under the following categories: antioxidants, erythropoietin and derivatives, lipids, riluzole, opioid antagonists, hormones, anti-inflammatory agents, statins, calpain inhibitors, hypothermia, and emerging strategies. Several clinical trials of neuroprotective agents have already taken place and have generally had disappointing results. In attempting to identify promising new treatments, we will therefore highlight agents with (1) low known risks or established clinical use, (2) behavioral data gained in clinically relevant animal models, (3) efficacy when administered after the injury, and (4) robust effects seen in more than one laboratory and/or more than one model of SCI.
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Hong Y, Palaksha KJ, Park K, Park S, Kim HD, Reiter RJ, Chang KT. Melatonin plus exercise-based neurorehabilitative therapy for spinal cord injury. J Pineal Res 2010; 49:201-9. [PMID: 20626592 DOI: 10.1111/j.1600-079x.2010.00786.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
Spinal cord injury (SCI) is damage to the spinal cord caused by the trauma or disease that results in compromised or loss of body function. Subsequent to SCI in humans, many individuals have residual motor and sensory deficits that impair functional performance and quality of life. The available treatments for SCI are rehabilitation therapy, activity-based therapies, and pharmacological treatment using antioxidants and their agonists. Among pharmacological treatments, the most efficient and commonly used antioxidant for experimental SCI treatment is melatonin, an indolamine secreted by pineal gland at night. Melatonin's receptor-independent free radical scavenging action and its broad-spectrum antioxidant activity makes it an ideal antioxidant to protect tissue from oxidative stress-induced secondary damage after SCI. Owing to the limitations of an activity-based therapy and antioxidant treatment singly on the functional recovery and oxidative stress-induced secondary damages after SCI, a melatonin plus exercise treatment may be a more effective therapy for SCI. As suggested herein, supplementation with melatonin in conjunction with exercise not only would improve the functional recovery by enhancing the beneficial effects of exercise but would reduce the secondary tissue damage simultaneously. Finally, melatonin may protect against exercise-induced fatigue and impairments. In this review, based on the documented evidence regarding the beneficial effects of melatonin, activity-based therapy and the combination of both on functional recovery, as well as reduction of secondary damage caused by oxidative stress after SCI, we suggest the melatonin combined with exercise would be a novel neurorehabilitative strategy for the faster recovery after SCI.
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Affiliation(s)
- Yonggeun Hong
- Department of Physical Therapy, Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, 607 O-bang Dong, Gimhae 621-749, Korea.
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Esposito E, Cuzzocrea S. Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol 2010; 8:228-42. [PMID: 21358973 PMCID: PMC3001216 DOI: 10.2174/157015910792246155] [Citation(s) in RCA: 287] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2010] [Revised: 04/25/2010] [Accepted: 05/08/2010] [Indexed: 12/15/2022] Open
Abstract
Melatonin is mainly produced in the mammalian pineal gland during the dark phase. Its secretion from the pineal gland has been classically associated with circadian and circanual rhythm regulation. However, melatonin production is not confined exclusively to the pineal gland, but other tissues including retina, Harderian glands, gut, ovary, testes, bone marrow and lens also produce it. Several studies have shown that melatonin reduces chronic and acute inflammation. The immunomodulatory properties of melatonin are well known; it acts on the immune system by regulating cytokine production of immunocompetent cells. Experimental and clinical data showing that melatonin reduces adhesion molecules and pro-inflammatory cytokines and modifies serum inflammatory parameters. As a consequence, melatonin improves the clinical course of illnesses which have an inflammatory etiology. Moreover, experimental evidence supports its actions as a direct and indirect antioxidant, scavenging free radicals, stimulating antioxidant enzymes, enhancing the activities of other antioxidants or protecting other antioxidant enzymes from oxidative damage. Several encouraging clinical studies suggest that melatonin is a neuroprotective molecule in neurodegenerative disorders where brain oxidative damage has been implicated as a common link. In this review, the authors examine the effect of melatonin on several neurological diseases with inflammatory components, including dementia, Alzheimer disease, Parkinson disease, multiple sclerosis, stroke, and brain ischemia/reperfusion but also in traumatic CNS injuries (traumatic brain and spinal cord injury).
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Affiliation(s)
- Emanuela Esposito
- Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy
| | - Salvatore Cuzzocrea
- Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy
- IRCCS Centro Neurolesi "Bonino-Pulejo", Messina, Italy
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Nesic O, Guest JD, Zivadinovic D, Narayana PA, Herrera JJ, Grill RJ, Mokkapati VUL, Gelman BB, Lee J. Aquaporins in spinal cord injury: the janus face of aquaporin 4. Neuroscience 2010; 168:1019-35. [PMID: 20109536 PMCID: PMC2885549 DOI: 10.1016/j.neuroscience.2010.01.037] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2009] [Revised: 01/16/2010] [Accepted: 01/19/2010] [Indexed: 02/07/2023]
Abstract
Although malfunction of spinal cord water channels (aquaporins, AQP) likely contributes to severe disturbances in ion/water homeostasis after spinal cord injury (SCI), their roles are still poorly understood. Here we report and discuss the potential significance of changes in the AQP4 expression in human SCI that generates glial fibrillary acidic protein (GFAP)-labeled astrocytes devoid of AQP4, and GFAP-labeled astroglia that overexpress AQP4. We used a rat model of contusion SCI to study observed changes in human SCI. AQP4-negative astrocytes are likely generated during the process of SCI-induced replacement of lost astrocytes, but their origin and role in SCI remains to be investigated. We found that AQP4-overexpression is likely triggered by hypoxia. Our transcriptional profiling of injured rat cords suggests that elevated AQP4-mediated water influx accompanies increased uptake of chloride and potassium ions which represents a protective astrocytic reaction to hypoxia. However, unbalanced water intake also results in astrocytic swelling that can contribute to motor impairment, but likely only in milder injuries. In severe rat SCI, a low abundance of AQP4-overexpressing astrocytes was found during the motor recovery phase. Our results suggest that severe rat contusion SCI is a better model to analyze AQP4 functions after SCI. We found that AQP4 increases in the chronic post-injury phase are associated with the development of pain-like behavior in SCI rats, while possible mechanisms underlying pain development may involve astrocytic swelling-induced glutamate release. In contrast, the formation and size of fluid-filled cavities occurring later after SCI does not appear to be affected by the extent of increased AQP4 levels. Therefore, the effect of therapeutic interventions targeting AQP4 will depend not only on the time interval after SCI or animal models, but also on the balance between protective role of increased AQP4 in hypoxia and deleterious effects of ongoing astrocytic swelling.
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Affiliation(s)
- O Nesic
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
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Fee DB, Swartz KR, Scheff N, Roberts K, Gabbita P, Scheff S. Melatonin-analog, β-methyl-6-chloromelatonin, supplementation in spinal cord injury. Brain Res 2010; 1340:81-5. [DOI: 10.1016/j.brainres.2010.04.047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2010] [Revised: 04/16/2010] [Accepted: 04/16/2010] [Indexed: 01/30/2023]
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Samantaray S, Das A, Thakore NP, Matzelle DD, Reiter RJ, Ray SK, Banik NL. Therapeutic potential of melatonin in traumatic central nervous system injury. J Pineal Res 2009; 47:134-142. [PMID: 19627458 PMCID: PMC11877319 DOI: 10.1111/j.1600-079x.2009.00703.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
A vast literature extolling the benefits of melatonin has accumulated during the past four decades. Melatonin was previously considered of importance to seasonal reproduction and circadian rhythmicity. Currently, it appears to be a versatile anti-oxidative and anti-nitrosative agent, a molecule with immunomodulatory actions and profound oncostatic activity, and also to play a role as a potent neuroprotectant. Nowadays, melatonin is sold as a dietary supplement with differential availability as an over-the-counter aid in different countries. There is a widespread agreement that melatonin is nontoxic and safe considering its frequent, long-term usage by humans at both physiological and pharmacological doses with no reported side effects. Endeavors toward a designated drug status for melatonin may be enormously rewarding in clinics for treatment of several forms of neurotrauma where effective pharmacological intervention has not yet been attained. This mini review consolidates the data regarding the efficacy of melatonin as an unique neuroprotective agent in traumatic central nervous system (CNS) injuries. Well-documented actions of melatonin in combating traumatic CNS damage are compiled from various clinical and experimental studies. Research on traumatic brain injury and ischemia/reperfusion are briefly outlined here as they have been recently reviewed elsewhere, whereas the studies on different animal models of the experimental spinal cord injury have been extensively covered in this mini review for the first time.
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Affiliation(s)
- Supriti Samantaray
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC
| | - Arabinda Das
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC
| | - Nakul P. Thakore
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC
| | - Denise D. Matzelle
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC
| | - Russel J. Reiter
- Department of Cellular and Structural Biology, University of Texas, San Antonio, TX
| | - Swapan K. Ray
- Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Naren L. Banik
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC
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Akhtar AZ, Pippin JJ, Sandusky CB. Animal studies in spinal cord injury: a systematic review of methylprednisolone. Altern Lab Anim 2009; 37:43-62. [PMID: 19292575 DOI: 10.1177/026119290903700108] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The objective of this study was to examine whether animal studies can reliably be used to determine the usefulness of methylprednisolone (MP) and other treatments for acute spinal cord injury (SCI) in humans. This was achieved by performing a systematic review of animal studies on the effects of MP administration on the functional outcome of acute SCI. Data were extracted from the published articles relating to: outcome; MP dosing regimen; species/strain; number of animals; methodological quality; type of injury induction; use of anaesthesia; functional scale used; and duration of follow-up. Subgroup analyses were performed, based on species or strain, injury method, MP dosing regimen, functional outcome measured, and methodological quality. Sixty-two studies were included, which involved a wide variety of animal species and strains. Overall, beneficial effects of MP administration were obtained in 34% of the studies, no effects in 58%, and mixed results in 8%. The results were inconsistent both among and within species, even when attempts were made to detect any patterns in the results through subgroup analyses. The results of this study demonstrate the barriers to the accurate prediction from animal studies of the effectiveness of MP in the treatment of acute SCI in humans. This underscores the need for the development and implementation of validated testing methods.
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Affiliation(s)
- Aysha Z Akhtar
- Physicians Committee for Responsible Medicine, Washington, DC, USA.
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Lin HW, Lee EJ. Effects of melatonin in experimental stroke models in acute, sub-acute, and chronic stages. Neuropsychiatr Dis Treat 2009; 5:157-62. [PMID: 19557110 PMCID: PMC2695239 DOI: 10.2147/ndt.s4815] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Melatonin (n-acetyl-5-methoxy-tryptamine), a naturally occurring indole produced mainly by the pineal gland, is a well known antioxidant. Stroke (cerebral ischemia) is the second leading cause of death worldwide. To date, however, effective and safe treatment for stroke remains unavailable. Melatonin is both lipid- and water-soluble and readily crosses the blood-brain barrier (BBB). Increasing evidence has shown that, in animal stroke models, administering melatonin significantly reduces infarct volume, edema, and oxidative damage and improves electrophysiological and behavioral performance. Here, we reviewed studies that assess effects of melatonin on cerebral ischemia in acute, sub-acute, and chronic stages. In addition to its potent antioxidant properties, melatonin exerts antiapoptotic, antiexcitotoxic, anti-inflammatory effects and promotes mitochondrial functions in animals with cerebral ischemia. Given that melatonin shows almost no toxicity to humans and possesses multifaceted protective capacity against cerebral ischemia, it is valuable to consider using melatonin in clinical trials on patients suffering from stroke.
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Affiliation(s)
- Hsiao-Wen Lin
- Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Medical Center and Medical School, Tainan, Taiwan
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Lack of neuroprotection with pharmacological pretreatment in a paradigm for anticipated spinal cord lesions. Spinal Cord 2008; 47:156-60. [DOI: 10.1038/sc.2008.85] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Samantaray S, Sribnick EA, Das A, Knaryan VH, Matzelle DD, Yallapragada AV, Reiter RJ, Ray SK, Banik NL. Melatonin attenuates calpain upregulation, axonal damage and neuronal death in spinal cord injury in rats. J Pineal Res 2008; 44:348-57. [PMID: 18086148 PMCID: PMC2613550 DOI: 10.1111/j.1600-079x.2007.00534.x] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Multiple investigations in vivo have shown that melatonin (MEL) has a neuroprotective effect in the treatment of spinal cord injury (SCI). This study investigates the role of MEL as an intervening agent for ameliorating Ca(2+)-mediated events, including activation of calpain, following its administration to rats sustaining experimental SCI. Calpain, a Ca(2+)-dependent neutral protease, is known to be involved in the pathogenesis of SCI. Rats were injured using a standard weight-drop method that induced a moderately severe injury (40 g.cm force) at T10. Sham controls received laminectomy only. Injured animals were given either 45 mg/kg MEL or vehicle at 15 min post-injury by intraperitoneal injection. At 48 hr post-injury, spinal cord (SC) samples were collected. Immunofluorescent labelings were used to identify calpain expression in specific cell types, such as neurons, glia, or macrophages. Combination of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) and double immunofluorescent labelings was used to identify apoptosis in specific cells in the SC. The effect of MEL on axonal damage was also investigated using antibody specific for dephosphorylated neurofilament protein (dNFP). Treatment of SCI animals with MEL attenuated calpain expression, inflammation, axonal damage (dNFP), and neuronal death, indicating that MEL provided neuroprotective effect in SCI. Further, expression and activity of calpain and caspse-3 were examined by Western blotting. The results indicated a significant decrease in expression and activity of calpain and caspse-3 in SCI animals after treatment with MEL. Taken together, this study strongly suggested that MEL could be an effective neuroprotective agent for treatment of SCI.
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Affiliation(s)
- Supriti Samantaray
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
| | - Eric A. Sribnick
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
| | - Arabinda Das
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
| | - Varduhi H. Knaryan
- Department of Neurohormones and Biochemistry, Buniatian Institute of Biochemistry, National Academy of Sciences of the Republic of Armenia, Yerevan, Republic of Armenia
| | - D. Denise Matzelle
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
| | - Anil V. Yallapragada
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
| | - Russel J. Reiter
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Swapan K. Ray
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
| | - Naren L. Banik
- Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
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Ates O, Cayli S, Gurses I, Yucel N, Altinoz E, Iraz M, Kocak A, Yologlu S. Does pinealectomy affect the recovery rate after spinal cord injury? Neurol Res 2008; 29:533-9. [PMID: 17535569 DOI: 10.1179/016164107x172121] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Previous reports documented demonstrated that melatonin, a free radical scavenger, is important in protecting against oxidative stress-induced tissue damage after spinal cord injury (SCI). This study was undertaken to investigate the effects of pinealectomy (PX) and administration of exogenous melatonin after SCI in rats. These animals were randomized into six groups, each having 12 rats. Group 1 underwent laminectomy alone. Group 2 underwent laminectomy followed by SCI and received no medication. Group 3 underwent laminectomy followed by SCI and received melatonin. Group 4 underwent PX and laminectomy alone. Group 5 underwent PX and laminectomy followed by SCI and received no medication. Group 6 underwent PX and laminectomy followed by SCI and received melatonin. Melatonin (100 mg/kg) was given intraperitoneally immediately after trauma to the rats in the groups 3 and 6. PX caused a significant increase in the malondialdehyde (MDA), nitrite oxide (NO), glutathione (GSH), xanthine oxidase (XO) levels and decrease in GSH levels as compared with the control group. Trauma to the spinal cord results in significantly higher oxidative stress. Melatonin administration significantly reduced MDA, XO and NO levels, and increased GSH levels in the spinal cord after trauma. Exogenous melatonin treatment after trauma attenuated tissue lesion area and accelerated motor recovery rate. These findings suggest that reduction in endogenous melatonin after PX makes the rats more vulnerable to trauma and exogenous melatonin administration has an important neuroprotective effect on the level of the spinal cord.
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Affiliation(s)
- Ozkan Ates
- Department of Neurosurgery, School of Medicine, Inonu University, Malatya, Turkey.
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Immunosuppression after traumatic or ischemic CNS damage: it is neuroprotective and illuminates the role of microglial cells. Prog Neurobiol 2007; 84:211-33. [PMID: 18262323 DOI: 10.1016/j.pneurobio.2007.12.001] [Citation(s) in RCA: 142] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2007] [Revised: 11/15/2007] [Accepted: 12/11/2007] [Indexed: 01/08/2023]
Abstract
Acute traumatic and ischemic events in the central nervous system (CNS) invariably result in activation of microglial cells as local representatives of the immune system. It is still under debate whether activated microglia promote neuronal survival, or whether they exacerbate the original extent of neuronal damage. Protagonists of the view that microglial cells cause secondary damage have proposed that inhibition of microglial activation by immunosuppression is beneficial after acute CNS damage. It is the aim of this review to analyse the effects of immunosuppressants on isolated microglial cells and neurons, and to scrutinize the effects of immunosuppression in different in vivo models of acute CNS trauma or ischemia. It is found that the immunosuppressants cytosine-arabinoside, different steroids, cyclosporin A, FK506, rapamycin, mycophenolate mofetil, and minocycline all have direct inhibitory effects on microglial cells. These effects are mainly exerted by inhibiting microglial proliferation or microglial secretion of neurotoxic substances such as proinflammatory cytokines and nitric oxide. Furthermore, immunosuppression after acute CNS trauma or ischemia results in improved structure preservation and, mostly, in enhanced function. However, all investigated immunosuppressants also have direct effects on neurons, and some immunosuppressants affect other glial cells such as astrocytes. In summary, it is safe to conclude that immunosuppression after acute CNS trauma or ischemia is neuroprotective. Furthermore, circumferential evidence indicates that microglial activation after traumatic or ischemic CNS damage is not beneficial to adjacent neurons in the immediate aftermath of such acute lesions. Further experiments with more specific agents or genetic approaches that specifically inhibit microglial cells are needed in order to fully answer the question of whether microglial activation is "good or bad".
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Ates O, Cayli SR, Gurses I, Turkoz Y, Tarim O, Cakir CO, Kocak A. Comparative neuroprotective effect of sodium channel blockers after experimental spinal cord injury. J Clin Neurosci 2007; 14:658-65. [PMID: 17532502 DOI: 10.1016/j.jocn.2006.03.023] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2006] [Accepted: 03/27/2006] [Indexed: 10/23/2022]
Abstract
Spinal cord injury (SCI) results in loss of function below the lesion. Secondary injury following the primary impact includes a number of biochemical and cellular alterations leading to tissue necrosis and cell death. Influx of Na(+) ions into cells has been postulated to be a key early event in the pathogenesis of secondary traumatic and ischemic central nervous system injury. Previous studies have shown that some voltage-sensitive sodium channel blockers provide powerful neuroprotection. The purpose of the present study was to compare the neuroprotective effect of three sodium channel blockers-mexiletine, phenytoin and riluzole--after SCI. Ninety rats were randomly and blindly divided into five groups of 18 rats each: sham-operated group, trauma group (bolus injection of 1 mL physiological saline intraperiteonally [i.p.]), mexiletine treatment group (80 mg/kg, i.p.), phenytoin treatment group (200 mg/kg, i.p.) and riluzole treatment group (8 mg/kg, i.p.). Twenty-four hours after injury, the rats were killed for determination of spinal cord water content and malondialdehyde (MDA) levels. Motor function scores of six rats from each group were evaluated weekly for six weeks. Then the rats were killed for histopathological assessment. Although all the treatment groups revealed significantly lower MDA levels and spinal cord edema than the trauma group (p<0.05), the riluzole and mexiletine treatment groups were better than the phenytoin treatment group. In the chronic stage, riluzole and mexiletine treatment achieved better results for neurobehavioral and histopathological recovery than phenytoin treatment. In conclusion, all the tested Na(+) blockers had a neuroprotective effect after SCI; riluzole and mexiletine were superior to phenytoin.
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Affiliation(s)
- Ozkan Ates
- Inonu University, School of Medicine, Department of Neurosurgery, Turgut Ozal Medical Center, 44069 Malatya, Turkey.
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Maldonado MD, Murillo-Cabezas F, Terron MP, Flores LJ, Tan DX, Manchester LC, Reiter RJ. The potential of melatonin in reducing morbidity-mortality after craniocerebral trauma. J Pineal Res 2007; 42:1-11. [PMID: 17198533 DOI: 10.1111/j.1600-079x.2006.00376.x] [Citation(s) in RCA: 145] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Craniocerebral trauma (CCT) is the most frequent cause of morbidity-mortality as a result of an accident. The probable origins and etiologies are multifactorial and include free radical formation and oxidative stress, the suppression of nonspecific resistance, lymphocytopenia (disorder in the adhesion and activation of cells), opportunistic infections, regional macro and microcirculatory alterations, disruptive sleep-wake cycles and toxicity caused by therapeutic agents. These pathogenic factors contribute to the unfavorable development of clinical symptoms as the disease progresses. Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine endogenously produced in the pineal gland and in other organs and it is protective agent against damage following CCT. Some of the actions of melatonin that support its pharmacological use after CCT include its role as a scavenger of both oxygen and nitrogen-based reactants, stimulation of the activities of a variety of antioxidative enzymes (e.g. superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase), inhibition of pro-inflammatory cytokines and activation-adhesion molecules which consequently reduces lymphocytopenia and infections by opportunistic organisms. The chronobiotic capacity of melatonin may also reset the natural circadian rhythm of sleep and wakefulness. Melatonin reduces the toxicity of the drugs used in the treatment of CCT and increases their efficacy. Finally, melatonin crosses the blood-brain barrier and reduces contusion volume and stabilizes cellular membranes preventing vasospasm and apoptosis of endothelial cells that occurs as a result of CCT.
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Affiliation(s)
- M D Maldonado
- Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX, USA, and Center for Rehabilitation and Traumatology of the Hospital University Virgen del Rocio, Seville, Spain.
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Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Kocak A, Yologlu S, Turkoz Y. Effects of resveratrol and methylprednisolone on biochemical, neurobehavioral and histopathological recovery after experimental spinal cord injury. Acta Pharmacol Sin 2006; 27:1317-25. [PMID: 17007738 DOI: 10.1111/j.1745-7254.2006.00416.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
AIM To investigate the neuroprotective effect of resveratrol in an experimental spinal cord injury (SCI) model in rats. METHODS Male Wistar albino rats weighing 200-250 g were randomized into six groups. Weight-drop trauma was performed for SCI. Group 1 underwent laminectomy alone. Group 2 underwent laminectomy followed by SCI. Groups 3, 4, 5, and 6 underwent laminectomy followed by SCI and received resveratrol (100 mg/kg), methylprednisolone (MP) (30 mg/kg), resveratrol (100 mg/kg) plus MP (30 mg/kg), and ethanol (2%), respectively. The rats were divided into two subgroups for biochemical analysis (killed at 24 h after surgery) and for neurobehavioral and histopathological evaluation (killed at 6 weeks after surgery). Posttraumatic neurological recovery after surgery was recorded weekly. RESULTS Groups 3 and 5 revealed significantly lower malon-dialdehyde, nitric oxide, xanthine oxidase, and higher glutathione levels than group 4 (P<0.05). Neurological recovery rates were significantly better in groups 3 and 5 than group 4 (P<0.05). When spinal trauma size ratios were compared, there was no significant difference between treatment groups. CONCLUSION Resveratrol treatment revealed better biochemical recovery in the acute stage of trauma than MP treatment. Although resveratrol and combined treatment revealed better neurobehavioral recovery than MP treatment; resveratrol, MP, and combined treatment modalities improved histopathological recovery at the same level in the final stage of the experiment. Future studies involving different doses of resveratrol and different doses combinations with MP could promise better results as each drug has a different anti-oxidative mechanism of action.
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Affiliation(s)
- Ozkan Ates
- Department of Neurosurgery, Inonu University, School of Medicine, 44280 Malatya, Turkey.
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Hagg T, Oudega M. Degenerative and spontaneous regenerative processes after spinal cord injury. J Neurotrauma 2006; 23:264-80. [PMID: 16629615 DOI: 10.1089/neu.2006.23.263] [Citation(s) in RCA: 205] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Spinal cord injury results in acute as well as progressive secondary destruction of local and distant nervous tissue through a number of degenerative mechanisms. Spinal cord injury also initiates a number of endogenous neuroprotective and regenerative responses. Understanding of these mechanisms might identify potential targets for treatments after spinal cord injury in humans. Here, we first discuss recent developments in our understanding of the immediate traumatic and subsequent secondary degeneration of local tissue and long projecting pathways in animal models. These include the inflammatory and vascular responses during the acute phase, as well as cell death, demyelination and scar formation in the subacute and chronic phases. Secondly, we discuss the spontaneous axonal regeneration of injured and plasticity of uninjured systems, and other repair-related responses in animals, including the upregulation of regeneration-associated genes in some neurons, increases in neurotrophic factors in the spinal cord and remyelination by oligodendrocyte precursors and invading Schwann cells. Lastly, we comment on the still limited understanding of the neuropathology in humans, which is largely similar to that in rodents. However, there also are potentially important differences, including the reduced glial scarring, inflammation and demyelination, the increased Schwannosis and the protracted Wallerian degeneration in humans. The validity of current rodent models for human spinal cord injury is also discussed. The emphasis of this review is on the literature from 2002 to early 2005.
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Affiliation(s)
- Theo Hagg
- Kentucky Spinal Cord Injury Research Center, Department of Neurological Surgery, University of Louisville, Louisville, Kentucky 40292, USA.
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Cayli SR, Ates O, Karadag N, Altinoz E, Yucel N, Yologlu S, Kocak A, Cakir CO. Neuroprotective effect of etomidate on functional recovery in experimental spinal cord injury. Int J Dev Neurosci 2006; 24:233-9. [PMID: 16701976 DOI: 10.1016/j.ijdevneu.2006.04.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2006] [Revised: 04/05/2006] [Accepted: 04/05/2006] [Indexed: 11/21/2022] Open
Abstract
OBJECTIVE Primary impact to the spinal cord causes rapid oxidative stress after injury. To protect neural tissue, it is important to prevent secondary pathophysiological mechanisms. Etomidate, a strong antiexcitotoxic agent, stimulates the gamma aminobutyric acid (GABA) receptors. The purpose of this study was to investigate neurobehavioral and histological recovery and to evaluate the biochemical responses to treatment of experimental spinal cord injury (SCI) in rats with etomidate or methylprednisolone (MP) or both etomidate and MP. MATERIAL AND METHODS Seventy-two rats were randomly allocated into six groups: a control group (laminectomy alone), a trauma group (laminectomy+trauma), a methylprednisolone group (30 mg/kg MP), an etomidate group (2 mg/kg), a methylprednisolone and etomidate combined treatment group (30 mg/kg MP and 2 mg/kg etomidate) and a vehicle group. Six rats from each group were killed at the 24th hour after the injury. Malondialdehyde, glutathione, nitric oxide and xanthine oxidase levels were measured. Neurological functions of the remaining rats were recorded weekly. Six weeks after injury, all of those rats were killed for histopathological assessment. RESULTS Etomidate treatment revealed similar neurobehavioral and histopathological recovery to MP treatment 6 weeks after injury. Combined treatment did not provide additional neuroprotection. CONCLUSION Etomidate treatment immediately after spinal cord injury has similar neuroprotection to MP. In spite of different neuroprotection mechanisms, combined treatment with MP and etomidate does not provide extra protection.
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Affiliation(s)
- Suleyman R Cayli
- Inonu University, School of Medicine, Department of Neurosurgery, Turgut Ozal Medical Center, 44069 Malatya, Turkey
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Gorio A, Madaschi L, Di Stefano B, Carelli S, Di Giulio AM, De Biasi S, Coleman T, Cerami A, Brines M. Methylprednisolone neutralizes the beneficial effects of erythropoietin in experimental spinal cord injury. Proc Natl Acad Sci U S A 2005; 102:16379-84. [PMID: 16260722 PMCID: PMC1283477 DOI: 10.1073/pnas.0508479102] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Inflammation plays a major pathological role in spinal cord injury (SCI). Although antiinflammatory treatment using the glucocorticoid methyprednisolone sodium succinate (MPSS) improved outcomes in several multicenter clinical trials, additional clinical experience suggests that MPSS is only modestly beneficial in SCI and poses a risk for serious complications. Recent work has shown that erythropoietin (EPO) moderates CNS tissue injury, in part by reducing inflammation, limiting neuronal apoptosis, and restoring vascular autoregulation. We determined whether EPO and MPSS act synergistically in SCI. Using a rat model of contusive SCI, we compared the effects of EPO [500-5,000 units/kg of body weight (kg-bw)] with MPSS (30 mg/kg-bw) for proinflammatory cytokine production, histological damage, and motor function at 1 month after a compression injury. Although high-dose EPO and MPSS suppressed proinflammatory cytokines within the injured spinal cord, only EPO was associated with reduced microglial infiltration, attenuated scar formation, and sustained neurological improvement. Unexpectedly, coadministration of MPSS antagonized the protective effects of EPO, even though the EPO receptor was up-regulated normally after injury. These data illustrate that the suppression of proinflammatory cytokines alone does not necessarily prevent secondary injury and suggest that glucocorticoids should not be coadministered in clinical trials evaluating the use of EPO for treatment of SCI.
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Affiliation(s)
- Alfredo Gorio
- Pharmacological Laboratories, Departments of Medicine, Surgery, and Dentistry, Polo Ospedale San Paolo, Faculty of Medicine, University of Milan, Via Celoria 26, 20133 Milan, Italy
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