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Alahdad N, Hamidpour SK, Yazdanpanah MA, Amiri M, Alizadeh R, Rezayat SM, Tavakol S. Nitric oxide synthases: A delicate dance between bone regeneration and neuronal birth. Biomed Pharmacother 2025; 187:118105. [PMID: 40294491 DOI: 10.1016/j.biopha.2025.118105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 03/23/2025] [Accepted: 04/24/2025] [Indexed: 04/30/2025] Open
Abstract
Spinal cord injury (SCI) is a devastating condition resulting from traumatic or nontraumatic injury/chronic disorder. The pathogenesis of SCI necessitates a comprehensive approach, as it involves therapeutic strategies addressing both bone (spine) and neural (spinal cord) damage. This review centers on the pivotal role of nitric oxide (NO) and its synthesizing enzymes, nitric oxide synthases (NOS), in mediating the crosstalk between osteogenesis and neurogenesis. NO's effects are context-dependent, exhibiting a delicate balance between beneficial and detrimental actions. Reduced levels of nitric oxide (NO), primarily derived from endothelial NOS (eNOS), tipically stimulate osteoblast activity and promote neurogenesis by influencing neural stem cell (NSC) migration and differentiation. Conversely, elevated NO levels, predominantly from inducible NOS (iNOS), tipically triggered by inflammation, inhibit both processes through pro-apoptotic mechanisms. Nevertheless, these phenomena are not merely simplistic; they can be influenced by a variety of other factors. We explore the intricate interplay of NO/NOS with key signaling pathways crucial in neurogenesis and osteogenesis, including mechanical stimuli, Wnt, interleukins, BMPs, NF-κB, etc., revealing their influence on neuroinflammation, neurogenesis, and osteoblast differentiation. The temporal and spatial dynamics of NO/NOS activity and the implications for therapeutic intervention have been discussed. Precise modulation of NO levels and NOS isoforms, potentially through targeted therapies manipulating these interacting signaling pathways, emerges as a promising strategy for promoting bone and neural regeneration. This review highlights the critical need for a balanced approach in therapeutic strategies to harness the beneficial effects of NO/NOS while mitigating its detrimental consequences.
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Affiliation(s)
- Niloofar Alahdad
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Shayesteh Kokabi Hamidpour
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Mohammad Ali Yazdanpanah
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Mobina Amiri
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Rafieh Alizadeh
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Mahdi Rezayat
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Shima Tavakol
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Research and Development, Tavakol BioMimetic Technologies Company, Tehran, Iran.
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Moradi F, Fakhri S, Kiani A, Abbaszadeh F, Farzaei MH, Echeverría J. Exploring the neuroprotective potential of naringin following spinal cord injury in rats: improving sensory and motor function through combating inflammation and oxidative stress. Front Pharmacol 2025; 16:1545049. [PMID: 40356950 PMCID: PMC12066580 DOI: 10.3389/fphar.2025.1545049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 04/08/2025] [Indexed: 05/15/2025] Open
Abstract
Introduction Spinal cord injury (SCI) leads to widespread cascades of inflammatory and oxidative factors. This pathological condition damages nerves and causes neurological disorders. To address these complex conditions, it is important to identify therapeutic candidates that affect multiple dysregulated signaling mediators and targets. Some phytochemicals such as naringin (NAI) with neuroprotective, antioxidant, and anti-inflammatory effects can be seen as a possible candidate for treating neurodegenerative diseases. Purpose Therefore, this study aims to evaluate the impact and mechanism of NAI on sensory and motor function in rats with SCI. Materials and methods In total, 35 rats were studied in five groups, including sham, SCI, and three groups treated with intrathecal administration of NAI (5, 10, and 15 mM). After the injury, sensorimotor behavioral tests and weight changes were performed for 4 weeks. On the 28th day, the serum of rats was checked to measure biochemical factors such as catalase, glutathione, and nitrite and the activity of metalloproteinases 2 (MMP-2) and MMP-9. Also, histological changes in spinal cord tissue were evaluated weekly for 4 weeks. Results and discussion NAI treatment demonstrated significant benefits in rats with SCI, including reducing pain, improvement in motor performance, and attenuated animal weight gain. Besides, NAI decreased the lesion area of spinal tissue and enhanced neuronal survival at both ventral and dorsal horns of spinal tissue. Furthermore, serum analysis revealed that NAI increased MMP-2 activity and catalase and glutathione levels while decreasing nitrite and MMP-9 activity. Conclusion The intrathecal administration of NAI can be proposed as a proper alternative in the treatment of sensory-motor disorders caused by SCI through neuroprotective, anti-inflammatory, and antioxidant mechanisms.
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Affiliation(s)
- Fatemeh Moradi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Amir Kiani
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Regenerative Medicine Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Abbaszadeh
- Neurobiology Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Javier Echeverría
- Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
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Ahmadpour Y, Bahrami G, Arkan E, Abbaszadeh F, Aghaz F, Fakhri S, Echeverría J. Unveiling the effects of Rosa canina oligosaccharide liposome on neuropathic pain and motor dysfunction following spinal cord injury in rats: relevance to its antioxidative effects. Front Pharmacol 2025; 16:1533025. [PMID: 40028155 PMCID: PMC11868053 DOI: 10.3389/fphar.2025.1533025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Accepted: 01/22/2025] [Indexed: 03/05/2025] Open
Abstract
Background Spinal cord injury (SCI) is a leading cause of sensorimotor disorders, impacting millions of people globally. The absence of effective treatments and the side effects of existing medications highlight the need for innovative research into new therapeutic compounds. Purpose Given the critical role of oxidative stress in the development of SCI and the antioxidant properties of oligosaccharides in other neurological disorders, this study focuses on the role of oxidative stress in SCI and explores the potential of a novel oligosaccharide nanoformulation derived from Rosa canina (Oligo-L). Materials and methods Oligo-L was formulated using soy lecithin as the phospholipid and the characterization included size, zeta potential, morphology, and drug loading efficiency. Then 35 Wistar male rats were divided into five groups of Sham, SCI, and Oligo-L (10 μL intrathecal injection of 15, 30, and 45 mg/mL). An aneurysm clip was used to induce compression injury of the SCI and Oligo-L groups. Sensory-motor functions were evaluated weekly for 4 weeks using tests such as the BBB scale, inclined plane, acetone drop, hot plate, von Frey, and monitoring of weight changes. Additionally, oxidative stress markers and histological changes were examined to evaluate changes in nitrite, glutathione, catalase, and neuronal survival. Results and discussion The findings indicated that Oligo-L treatment led to significant improvements in neuropathic pain, and motor function performance and weight of the animals from the first week post-SCI. Oligo-L also enhanced catalase and glutathione levels while reducing serum nitrite levels, contributing to neuronal preservation. Additionally, Oligo-L increased neuronal survival in the both ventral (motor neurons) and dorsal (sensory neurons) horns of the spinal cord. Conclusion Overall, Oligo-L, characterized by its beneficial physicochemical properties, showed promising potential as a neuroprotective agent and facilitated the recovery of sensory and motor functions after SCI.
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Affiliation(s)
- Yasaman Ahmadpour
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Gholamreza Bahrami
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Elham Arkan
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Abbaszadeh
- Neurobiology Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Faranak Aghaz
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Javier Echeverría
- Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
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Rezaiezadeh H, Langarizadeh MA, Tavakoli MR, Sabokro M, Banazadeh M, Kohlmeier KA, Shabani M. Therapeutic potential of Bergenin in the management of neurological-based diseases and disorders. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8349-8366. [PMID: 38850305 DOI: 10.1007/s00210-024-03197-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 05/28/2024] [Indexed: 06/10/2024]
Abstract
Originally sourced from plants, Bergenin has been used as a medicinal compound in traditional medicine for centuries, and anecdotal reports suggest a wide range of therapeutic uses. Naturally-occurring and lab-synthesized Bergenin, as well as some of its related compounds, have been shown in in vivo and in vitro studies to alter activity of several enzymes and proteins critical in cellular functioning, including reelin, GSK-3β, Lingo-1, Ten-4, GP-43, Aβ 1-42, P-tau, SOD1,2, GPx, Glx1, NQO1, HO1, PPAR-ɣ, BDNF, VEGF, and STAT6. Additionally, Bergenin alters levels of several cytokines, such as IL-6, IL-1β, TNF-α, and TGF-β. Behavioral and cellular effects of Bergenin have been shown to involve PI3K/Akt, NF-κB, PKC, Nrf2, and Sirt1/FOXO3a pathways. These pathways, enzymes, and proteins have been shown to be important in normal neurological functioning, and/or dysfunctions in these pathways and proteins have been shown to be important in several neuro-based disorders or diseases, which suggests that Bergenin could be therapeutic in management of neuropsychiatric conditions or neurological disorders. In preclinical studies, Bergenin has been shown to be useful for the management of Alzheimer's disease, Parkinson's disease, anxiety, depression, addiction, epilepsy, insomnia, stroke, and potentially, state control. Our review aims to summarize current evidence supporting the conclusion that Bergenin could play a role in treating various neuro-based disorders and that future studies should be conducted to evaluate the mechanisms by which Bergenin could exert its therapeutic effects.
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Affiliation(s)
- Hojjat Rezaiezadeh
- Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, P.O. Box, Shiraz, 71345-1583, Iran
| | - Mohammad Amin Langarizadeh
- Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutics Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Marziye Ranjbar Tavakoli
- Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutics Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Sabokro
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammad Banazadeh
- Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Kristi A Kohlmeier
- Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mohammad Shabani
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran.
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran.
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Yan Y, Li Z, Zhang S, Bai F, Jing Y, Huang F, Yu Y. Remote limb ischemic preconditioning alleviated spinal cord injury through inhibiting proinflammatory immune response and promoting the survival of spinal neurons. Spinal Cord 2024; 62:562-573. [PMID: 39154149 DOI: 10.1038/s41393-024-01015-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 06/18/2024] [Accepted: 07/09/2024] [Indexed: 08/19/2024]
Abstract
STUDY DESIGN Experimental animal study. OBJECTIVES To investigate the protective effect of remote limb ischemia preconditioning (RLPreC) on traumatic spinal cord injury (SCI) and explore the underlying biological mechanisms using RNA sequencing. SETTING China Rehabilitation Science Institute; Beijing; China. METHODS spinal cord injury was induced in mice using a force of 0.7 N. RLPreC treatment was administered. Motor function, pain behavior, and gene expression were assessed. RESULTS RLPreC treatment significantly improved motor function and reduced pain-like behavior in SCI mice. RNA-Seq analysis identified 5247 differentially expressed genes (DEGs). GO analysis revealed enrichment of immune response, inflammatory signaling, and synaptic transmission pathways among these DEGs. KEGG analysis indicated suppression of inflammation and promotion of synapse-related pathways. CONCLUSIONS RLPreC is a promising therapeutic strategy for improving motor function and alleviating pain after traumatic SCI. RNA-Seq analysis provides insights into potential therapeutic targets and warrants further investigation.
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Affiliation(s)
- Yitong Yan
- China Rehabilitation Science Institute, Beijing, People's Republic of China
- China Rehabilitation Research Center, Beijing, People's Republic of China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, People's Republic of China
- School of Rehabilitation Medicine, Capital Medical University, Beijing, People's Republic of China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, People's Republic of China
| | - Zihan Li
- China Rehabilitation Science Institute, Beijing, People's Republic of China
- China Rehabilitation Research Center, Beijing, People's Republic of China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, People's Republic of China
- School of Rehabilitation Medicine, Capital Medical University, Beijing, People's Republic of China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, People's Republic of China
| | - Shuangyue Zhang
- China Rehabilitation Science Institute, Beijing, People's Republic of China
- China Rehabilitation Research Center, Beijing, People's Republic of China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, People's Republic of China
- School of Rehabilitation Medicine, Capital Medical University, Beijing, People's Republic of China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, People's Republic of China
| | - Fan Bai
- China Rehabilitation Science Institute, Beijing, People's Republic of China
- China Rehabilitation Research Center, Beijing, People's Republic of China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, People's Republic of China
- School of Rehabilitation Medicine, Capital Medical University, Beijing, People's Republic of China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, People's Republic of China
| | - Yingli Jing
- China Rehabilitation Science Institute, Beijing, People's Republic of China
- China Rehabilitation Research Center, Beijing, People's Republic of China
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, People's Republic of China
- School of Rehabilitation Medicine, Capital Medical University, Beijing, People's Republic of China
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, People's Republic of China
| | - Fubiao Huang
- China Rehabilitation Research Center, Beijing, People's Republic of China
- School of Rehabilitation Medicine, Capital Medical University, Beijing, People's Republic of China
| | - Yan Yu
- China Rehabilitation Science Institute, Beijing, People's Republic of China.
- China Rehabilitation Research Center, Beijing, People's Republic of China.
- Beijing Key Laboratory of Neural Injury and Rehabilitation, Beijing, People's Republic of China.
- School of Rehabilitation Medicine, Capital Medical University, Beijing, People's Republic of China.
- Center of Neural Injury and Repair, Beijing Institute for Brain Disorders, Beijing, People's Republic of China.
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Wen X, Ye Y, Yu Z, Shen H, Cui G, Chen G. The role of nitric oxide and hydrogen sulfide in spinal cord injury: an updated review. Med Gas Res 2024; 14:96-101. [PMID: 39073336 PMCID: PMC466995 DOI: 10.4103/2045-9912.385946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 12/16/2022] [Accepted: 04/04/2023] [Indexed: 07/30/2024] Open
Abstract
Medical gases play an important role in the pathophysiology of human diseases and have received extensive attention for their role in neuroprotection. Common pathological mechanisms of spinal cord injury include excitotoxicity, inflammation, cell death, glial scarring, blood-spinal cord barrier disruption, and ischemia/reperfusion injury. Nitric oxide and hydrogen sulfide are important gaseous signaling molecules in living organisms; their pathological role in spinal cord injury models has received more attention in recent years. This study reviews the possible mechanisms of spinal cord injury and the role of nitric oxide and hydrogen sulfide in spinal cord injury.
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Affiliation(s)
- Xiaoliang Wen
- Brain and Nerve Research Laboratory, Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Yang Ye
- Brain and Nerve Research Laboratory, Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Zhengquan Yu
- Brain and Nerve Research Laboratory, Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Haitao Shen
- Brain and Nerve Research Laboratory, Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Gang Cui
- Brain and Nerve Research Laboratory, Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
| | - Gang Chen
- Brain and Nerve Research Laboratory, Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, China
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Bagheri Bavandpouri FS, Azizi A, Abbaszadeh F, Kiani A, Farzaei MH, Mohammadi-Noori E, Fakhri S, Echeverría J. Polydatin attenuated neuropathic pain and motor dysfunction following spinal cord injury in rats by employing its anti-inflammatory and antioxidant effects. Front Pharmacol 2024; 15:1452989. [PMID: 39193334 PMCID: PMC11347411 DOI: 10.3389/fphar.2024.1452989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 07/31/2024] [Indexed: 08/29/2024] Open
Abstract
Background Considering the complex pathological mechanisms behind spinal cord injury (SCI) and the adverse effects of present non-approved drugs against SCI, new studies are needed to introduce novel multi-target active ingredients with higher efficacy and lower side effects. Polydatin (PLD) is a naturally occurring stilbenoid glucoside recognized for its antioxidative and anti-inflammatory properties. This study aimed to assess the effects of PLD on sensory-motor function following SCI in rats. Methods Following laminectomy and clip compression injury at the thoracic 8 (T8)-T9 level of the spinal cord, rats were randomly assigned to five groups: Sham, SCI, and three groups receiving different doses of PLD treatment (1, 2, and 3 mg/kg). Over 4 weeks, behavioral tests were done such as von Frey, acetone drop, hot plate, Basso-Beattie-Bresnahan, and inclined plane test. At the end of the study, changes in catalase and glutathione activity, nitrite level, activity of matrix metalloproteinase 2 (MMP2) and MMP9 as well as spinal tissue remyelination/neurogenesis, were evaluated. Results The results revealed that PLD treatment significantly improved the behavioral performance of the animals starting from the first week after SCI. Additionally, PLD increased catalase, and glutathione levels, and MMP2 activity while reduced serum nitrite levels and MMP9. These positive effects were accompanied by a reduction in the size of the lesion and preservation of neuronal count. Conclusion In conclusion, PLD showed neuroprotective effects in SCI rats by employing anti-inflammatory and antioxidant effects, through which improve sensory and motor function.
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Affiliation(s)
| | - Atefeh Azizi
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Abbaszadeh
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Kiani
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Regenerative Medicine Research Center (RMRC), Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ehsan Mohammadi-Noori
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Javier Echeverría
- Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
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Jakubek P, Parchem K, Wieckowski MR, Bartoszek A. The Interplay between Endogenous and Foodborne Pro-Oxidants and Antioxidants in Shaping Redox Homeostasis. Int J Mol Sci 2024; 25:7827. [PMID: 39063068 PMCID: PMC11276820 DOI: 10.3390/ijms25147827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/11/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Oxidative stress has been known about in biological sciences for several decades; however, the understanding of this concept has evolved greatly since its foundation. Over the past years, reactive oxygen species, once viewed as solely deleterious, have become recognized as intrinsic components of life. In contrast, antioxidants, initially believed to be cure-all remedies, have failed to prove their efficacy in clinical trials. Fortunately, research on the health-promoting properties of antioxidants has been ongoing. Subsequent years showed that the former assumption that all antioxidants acted similarly was greatly oversimplified. Redox-active compounds differ in their chemical structures, electrochemical properties, mechanisms of action, and bioavailability; therefore, their efficacy in protecting against oxidative stress also varies. In this review, we discuss the changing perception of oxidative stress and its sources, emphasizing everyday-life exposures, particularly those of dietary origin. Finally, we posit that a better understanding of the physicochemical properties and biological outcomes of antioxidants is crucial to fully utilize their beneficial impact on health.
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Affiliation(s)
- Patrycja Jakubek
- Department of Food Chemistry, Technology and Biotechnology, Faculty of Chemistry, Gdańsk University of Technology, 80-233 Gdańsk, Poland;
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland;
| | - Karol Parchem
- Department of Food Chemistry, Technology and Biotechnology, Faculty of Chemistry, Gdańsk University of Technology, 80-233 Gdańsk, Poland;
| | - Mariusz R. Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland;
| | - Agnieszka Bartoszek
- Department of Food Chemistry, Technology and Biotechnology, Faculty of Chemistry, Gdańsk University of Technology, 80-233 Gdańsk, Poland;
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Yu T, Yang LL, Zhou Y, Wu MF, Jiao JH. Exosome-mediated repair of spinal cord injury: a promising therapeutic strategy. Stem Cell Res Ther 2024; 15:6. [PMID: 38167108 PMCID: PMC10763489 DOI: 10.1186/s13287-023-03614-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 12/12/2023] [Indexed: 01/05/2024] Open
Abstract
Spinal cord injury (SCI) is a catastrophic injury to the central nervous system (CNS) that can lead to sensory and motor dysfunction, which seriously affects patients' quality of life and imposes a major economic burden on society. The pathological process of SCI is divided into primary and secondary injury, and secondary injury is a cascade of amplified responses triggered by the primary injury. Due to the complexity of the pathological mechanisms of SCI, there is no clear and effective treatment strategy in clinical practice. Exosomes, which are extracellular vesicles of endoplasmic origin with a diameter of 30-150 nm, play a critical role in intercellular communication and have become an ideal vehicle for drug delivery. A growing body of evidence suggests that exosomes have great potential for repairing SCI. In this review, we introduce exosome preparation, functions, and administration routes. In addition, we summarize the effect and mechanism by which various exosomes repair SCI and review the efficacy of exosomes in combination with other strategies to repair SCI. Finally, the challenges and prospects of the use of exosomes to repair SCI are described.
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Affiliation(s)
- Tong Yu
- Department of Orthopedic, The Second Norman Bethune Hospital of Jilin University, Changchun, 130000, Jilin Province, China
| | - Li-Li Yang
- Department of Orthopedic, The Second Norman Bethune Hospital of Jilin University, Changchun, 130000, Jilin Province, China
| | - Ying Zhou
- Department of Operating Room, The Third Hospital of Qinhuangdao, Qinhuangdao, 066000, Hebei Province, China
| | - Min-Fei Wu
- Department of Orthopedic, The Second Norman Bethune Hospital of Jilin University, Changchun, 130000, Jilin Province, China
| | - Jian-Hang Jiao
- Department of Orthopedic, The Second Norman Bethune Hospital of Jilin University, Changchun, 130000, Jilin Province, China.
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Sharma HS, Muresanu DF, Nozari A, Lafuente JV, Buzoianu AD, Tian ZR, Huang H, Feng L, Bryukhovetskiy I, Manzhulo I, Wiklund L, Sharma A. Neuroprotective Effects of Nanowired Delivery of Cerebrolysin with Mesenchymal Stem Cells and Monoclonal Antibodies to Neuronal Nitric Oxide Synthase in Brain Pathology Following Alzheimer's Disease Exacerbated by Concussive Head Injury. ADVANCES IN NEUROBIOLOGY 2023; 32:139-192. [PMID: 37480461 DOI: 10.1007/978-3-031-32997-5_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/24/2023]
Abstract
Concussive head injury (CHI) is one of the major risk factors in developing Alzheimer's disease (AD) in military personnel at later stages of life. Breakdown of the blood-brain barrier (BBB) in CHI leads to extravasation of plasma amyloid beta protein (ΑβP) into the brain fluid compartments precipitating AD brain pathology. Oxidative stress in CHI or AD is likely to enhance production of nitric oxide indicating a role of its synthesizing enzyme neuronal nitric oxide synthase (NOS) in brain pathology. Thus, exploration of the novel roles of nanomedicine in AD or CHI reducing NOS upregulation for neuroprotection are emerging. Recent research shows that stem cells and neurotrophic factors play key roles in CHI-induced aggravation of AD brain pathologies. Previous studies in our laboratory demonstrated that CHI exacerbates AD brain pathology in model experiments. Accordingly, it is quite likely that nanodelivery of NOS antibodies together with cerebrolysin and mesenchymal stem cells (MSCs) will induce superior neuroprotection in AD associated with CHI. In this review, co-administration of TiO2 nanowired cerebrolysin - a balanced composition of several neurotrophic factors and active peptide fragments, together with MSCs and monoclonal antibodies (mAb) to neuronal NOS is investigated for superior neuroprotection following exacerbation of brain pathology in AD exacerbated by CHI based on our own investigations. Our observations show that nanowired delivery of cerebrolysin, MSCs and neuronal NOS in combination induces superior neuroprotective in brain pathology in AD exacerbated by CHI, not reported earlier.
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Affiliation(s)
- Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania
- "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Ala Nozari
- Anesthesiology & Intensive Care, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA
| | - José Vicente Lafuente
- LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA
| | - Hongyun Huang
- Beijing Hongtianji Neuroscience Academy, Beijing, China
| | - Lianyuan Feng
- Department of Neurology, Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China
| | - Igor Bryukhovetskiy
- Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia
| | - Igor Manzhulo
- Laboratory of Pharmacology, National Scientific Center of Marine Biology, Far East Branch of the Russian Academy of Sciences, Vladivostok, Russia
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
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Hsu CC, Tsai CC, Ko PY, Kwan TH, Liu MY, Wu PT, Jou IM. Triptolide Attenuates Muscular Inflammation and Oxidative Stress in a Delayed-Onset Muscle Soreness Animal Model. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:16685. [PMID: 36554566 PMCID: PMC9778903 DOI: 10.3390/ijerph192416685] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/07/2022] [Accepted: 12/08/2022] [Indexed: 06/17/2023]
Abstract
Delayed-onset muscle soreness (DOMS) is associated with exercise-induced muscle damage and inflammation, which is mainly caused by prolonged eccentric exercise in humans. Triptolide, an extract from the Chinese herb Tripterygium wilfordii Hook F, has been used for treating autoimmune and inflammatory diseases in clinical practice. However, whether triptolide attenuates acute muscle damage is still unclear. Here, we examined the effect of triptolide on carrageenan-induced DOMS in rats. Rats were injected with 3% of carrageenan into their muscles to induce acute left gastrocnemius muscular damage, and triptolide treatment attenuated carrageenan-induced acute muscular damage without affecting hepatic function. Triptolide can significantly decrease lipid hydroperoxide and nitric oxide (NO) levels, proinflammatory cytokine production, and the activation of nuclear factor (NF)-ĸB, as well as increase a reduced form of glutathione levels in carrageenan-treated rat muscles. At the enzyme levels, triptolide reduced the inducible nitric oxide synthase (iNOS) expression and muscular myeloperoxidase (MPO) activity in carrageenan-treated DOMS rats. In conclusion, we show that triptolide can attenuate muscular damage by inhibiting muscular oxidative stress and inflammation in a carrageenan-induced rat DOMS model.
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Affiliation(s)
- Che-Chia Hsu
- Department of Orthopaedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
| | - Chin-Chuan Tsai
- Department of Traditional Chinese Medicine, E-Da Dachang Hospital, Kaohsiung 82445, Taiwan
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
| | - Po-Yen Ko
- Department of Orthopaedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
| | - Ting-Hsien Kwan
- Department of Orthopaedics, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 60002, Taiwan
| | - Ming-Yie Liu
- Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
| | - Po-Ting Wu
- Department of Orthopaedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
- Medical Device Innovation Center, National Cheng Kung University, Tainan 70428, Taiwan
- Department of Orthopaedics, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
- Department of Biomedical Engineering, National Cheng Kung University, Tainan 70428, Taiwan
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70428, Taiwan
| | - I-Ming Jou
- Department of Orthopaedics, E-Da Hospital, Kaohsiung 82445, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan
- GEG Orthopedic Clinic, Tainan 74543, Taiwan
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12
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Antinociceptive effect of N-acetyl glucosamine in a rat model of neuropathic pain. Acta Neuropsychiatr 2022; 34:260-268. [PMID: 35109948 DOI: 10.1017/neu.2022.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVE This study was aimed at evaluating the efficacy of glucosamine and potential mechanisms of actions in a neuropathic pain model in rats. METHODS Glucosamine (500, 1000 and 2000 mg/kg) was administered via gavage route, 1 day before the chronic constriction injury (CCI) of sciatic nerve and daily for 14 days (prophylactic regimen), or from days 5 to 14 post-injury (therapeutic regimen), as the indicators of neuropathic pain, mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed on days 0, 3, 5, 7, 10 and 14 after ligation. Inducible nitric oxide synthase (iNOS) and tumour necrosis factor alpha (TNF-α) gene expressions were measured by real-time polymerase chain reaction. TNF-α protein content was measured using the enzyme-linked immunosorbent assay method. RESULTS Three days after nerve injury, the threshold of pain was declined among animals subjected to neuropathic pain. Mechanical and cold allodynia, as well as thermal hyperalgesia were attenuated by glucosamine (500, 1000, 2000 mg/kg) in the prophylactic regimen. However, existing pain was not decreased by this drug. Increased mRNA expression of iNOS and TNF-α was significantly reduced in the spinal cord of CCI animals by glucosamine (500, 1000, 2000 mg/kg) in the prophylactic regimen. The overall expression of spinal TNF-α was increased by CCI, but this increase was reduced in animals receiving glucosamine prophylactic treatment. CONCLUSION Findings suggest that glucosamine as a safe supplement may be a useful candidate in preventing neuropathic pain following nerve injury. Antioxidant and anti-inflammatory effects may be at least in part responsible for the antinociceptive effects of this drug.
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13
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Arias F, Camacho ME, Carrión MD. NMR spectroscopy study of new imidamide derivatives as nitric oxide synthase inhibitors. MAGNETIC RESONANCE IN CHEMISTRY : MRC 2022; 60:915-923. [PMID: 35428991 DOI: 10.1002/mrc.5273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 03/30/2022] [Accepted: 04/02/2022] [Indexed: 06/14/2023]
Affiliation(s)
- Fabio Arias
- Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Granada, Spain
| | - María Encarnación Camacho
- Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Granada, Spain
| | - María Dora Carrión
- Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Granada, Spain
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Perovic D, Milavic M, Dokuzovic S, Krezic I, Gojkovic S, Vranes H, Bebek I, Bilic V, Somun N, Brizic I, Skorak I, Hriberski K, Sikiric S, Lovric E, Strbe S, Kubat M, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. Novel Therapeutic Effects in Rat Spinal Cord Injuries: Recovery of the Definitive and Early Spinal Cord Injury by the Administration of Pentadecapeptide BPC 157 Therapy. Curr Issues Mol Biol 2022; 44:1901-1927. [PMID: 35678659 PMCID: PMC9164058 DOI: 10.3390/cimb44050130] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/22/2022] [Accepted: 04/24/2022] [Indexed: 12/17/2022] Open
Abstract
Recently, marked therapeutic effects pertaining to the recovery of injured rat spinal cords (1 min compression injury of the sacrocaudal spinal cord (S2-Co1) resulting in tail paralysis) appeared after a single intraperitoneal administration of the stable gastric pentadecapeptide BPC 157 at 10 min post-injury. Besides the demonstrated rapid and sustained recovery (1 year), we showed the particular points of the immediate effect of the BPC 157 therapy that began rapidly after its administration, (i) soon after injury (10 min), or (ii) later (4 days), in the rats with a definitive spinal cord injury. Specifically, in counteracting spinal cord hematoma and swelling, (i) in rats that had undergone acute spinal cord injury, followed by intraperitoneal BPC 157 application at 10 min, we focused on the first 10-30 min post-injury period (assessment of gross, microscopic, and gene expression changes). Taking day 4 post-injury as the definitive injury, (ii) we focused on the immediate effects after the BPC 157 intragastric application over 20 min of the post-therapy period. Comparable long-time recovery was noted in treated rats which had definitive tail paralysis: (iii) the therapy was continuously given per orally in drinking water, beginning at day 4 after injury and lasting one month after injury. BPC 157 rats presented only discrete edema and minimal hemorrhage and increased Nos1, Nos2, and Nos3 values (30 min post-injury, (i)) or only mild hemorrhage, and only discrete vacuolation of tissue (day 4, (ii)). In the day 4-30 post-injury study (iii), BPC 157 rats rapidly presented tail function recovery, and no demyelination process (Luxol fast blue staining).
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Affiliation(s)
- Darko Perovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
- Department of Surgery, Clinical Hospital Dubrava, 10000 Zagreb, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Stjepan Dokuzovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Igor Bebek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Vide Bilic
- Clinical Hospital of Traumatology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia;
| | - Nenad Somun
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Ivan Brizic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Ivan Skorak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Klaudija Hriberski
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Milovan Kubat
- Department of Forensic Medicine and Criminology, School of Medicine, 10000 Zagreb, Croatia;
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
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15
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Progression in translational research on spinal cord injury based on microenvironment imbalance. Bone Res 2022; 10:35. [PMID: 35396505 PMCID: PMC8993811 DOI: 10.1038/s41413-022-00199-9] [Citation(s) in RCA: 106] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 11/14/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Spinal cord injury (SCI) leads to loss of motor and sensory function below the injury level and imposes a considerable burden on patients, families, and society. Repair of the injured spinal cord has been recognized as a global medical challenge for many years. Significant progress has been made in research on the pathological mechanism of spinal cord injury. In particular, with the development of gene regulation, cell sequencing, and cell tracing technologies, in-depth explorations of the SCI microenvironment have become more feasible. However, translational studies related to repair of the injured spinal cord have not yielded significant results. This review summarizes the latest research progress on two aspects of SCI pathology: intraneuronal microenvironment imbalance and regenerative microenvironment imbalance. We also review repair strategies for the injured spinal cord based on microenvironment imbalance, including medications, cell transplantation, exosomes, tissue engineering, cell reprogramming, and rehabilitation. The current state of translational research on SCI and future directions are also discussed. The development of a combined, precise, and multitemporal strategy for repairing the injured spinal cord is a potential future direction.
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Wang G, Chen S, Shao Z, Li Y, Wang W, Mao L, Li J, Mei X. Metformin alleviates hydrogen peroxide-induced inflammation and oxidative stress via inhibiting P2X7R signaling in spinal cord tissue cells neurons. Can J Physiol Pharmacol 2021; 99:768-774. [PMID: 33201730 DOI: 10.1139/cjpp-2020-0373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Metformin, the first medication that is often prescribed for the treatment of type 2 diabetes mellitus, was recently found to be neuroprotective. To study the mechanism underlying the neuroprotective effect of metformin, we pretreated primary spinal cord neurons with 50 µM or 100 µM metformin for 2 h prior to treatment with hydrogen peroxide (H2O2) for up to 48 h. Our results showed that H2O2 increased the expression of purinergic receptor P2X7 (P2X7R) in spinal cord neurons, which promoted the downstream pro-inflammatory cytokines release and oxidative stress. We found that metformin could reverse these pro-inflammatory and pro-oxidative effects of H2O2. Besides, P2X7R knockdown by siRNA suppressed H2O2-induced pro-inflammatory cytokine release and oxidative stress response. In conclusion, our results show that metformin can alleviate H2O2-induced inflammation and oxidative stress via modulating the P2X7R signaling pathway.
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Affiliation(s)
- Gang Wang
- Department of Orthopedics, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, 121000, China
- Department of Orthopedic, Maanshan People's Hospital, Ma'anshan City, China
| | - Shurui Chen
- Jinzhou Medical University, Jinzhou City, 121000, China
| | - Zhenya Shao
- Department of Orthopedics, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, 121000, China
| | - Yankun Li
- Department of Orthopedics, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, 121000, China
| | - Wei Wang
- Department of Orthopedics, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, 121000, China
| | - Liang Mao
- Department of Oncology, Key Laboratory of Medical Tissue Engineering of Liaoning Province, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, China
| | - Jian Li
- Department of Orthopedic, Maanshan People's Hospital, Ma'anshan City, China
| | - Xifan Mei
- Department of Orthopedics, First Affiliated Hospital of Jinzhou Medical University, Jinzhou City, 121000, China
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Topical application of CNTF, GDNF and BDNF in combination attenuates blood-spinal cord barrier permeability, edema formation, hemeoxygenase-2 upregulation, and cord pathology. PROGRESS IN BRAIN RESEARCH 2021; 266:357-376. [PMID: 34689864 DOI: 10.1016/bs.pbr.2021.06.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Spinal cord injury (SCI) is one of the leading causes of disability in Military personnel for which no suitable therapeutic strategies are available till today. Thus, exploration of novel therapeutic measures is highly needed to enhance the quality of life of SCI victims. Previously, topical application of BDNF and GDNF in combination over the injured spinal cord after 90min induced marked neuroprotection. In present investigation, we added CNTF in combination with BDNF and/or GDNF treatment to examine weather the triple combination applied over the traumatic cord after 90 or 120min could thwart cord pathology. Since neurotrophins attenuate nitric oxide (NO) production in SCI, the role of carbon monoxide (CO) production that is similar to NO in inducing cell injury was explored using immunohistochemistry of the constitutive isoform of enzyme hemeoxygenase-2 (HO-2). SCI inflicted over the right dorsal horn of the T10-11 segments by making an incision of 2mm deep and 5mm long upregulated the HO-2 immunostaining in the T9 and T12 segments after 5h injury. These perifocal segments are associated with breakdown of the blood-spinal cord barrier (BSCB), edema development and cell injuries. Topical application of CNTF with BDNF and GDNF in combination (10ng each) after 90 and 120min over the injured spinal cord significantly attenuated the BSCB breakdown, edema formation, cell injury and overexpression of HO-2. These observations are the first to show that CNTF with BDNF and GDNF induced superior neuroprotection in SCI probably by downregulation of CO production, not reported earlier.
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18
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Huang Z, Ji H, Shi J, Zhu X, Zhi Z. Engeletin Attenuates Aβ1-42-Induced Oxidative Stress and Neuroinflammation by Keap1/Nrf2 Pathway. Inflammation 2021; 43:1759-1771. [PMID: 32445069 DOI: 10.1007/s10753-020-01250-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Alzheimer's disease (AD) is a serious neuropathologic disease characterized by aggregation of amyloid-β (Aβ) peptide. Aβ-mediated oxidative stress and neuroinflammation play crucial role in the development of AD. Engeletin is a flavononol glycoside that possesses anti-inflammatory effect. However, the effects of engeletin on AD have not been investigated. In the present study, we investigated the role of engeletin in AD using an in vitro AD model. Murine microglia BV-2 cells were stimulated with Aβ1-42 (5 μM) for 24 h to induce oxidative stress and inflammation. Our results showed that treatment with engeletin suppressed Aβ1-42-induced viability reduction and lactate dehydrogenase (LDH) release in BV-2 cells. Engeletin attenuated Aβ1-42-induced oxidative stress in BV-2 cells, as proved by decreased production of reactive oxygen species (ROS) and malonaldehyde (MDA) and increased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. Aβ1-42-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression were inhibited by engeletin treatment. Besides, engeletin inhibited Aβ1-42-induced production and mRNA levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6). Engeletin enhanced Aβ1-42-induced activation of Kelch-like ECH-associated protein 1 (Keap1)/nuclear transcription factor E2-related factor 2 (Nrf2) signaling pathway in BV-2 cells. Inhibition of Keap1/Nrf2 signaling pathway reversed the inhibitory effects of engeletin on Aβ1-42-induced oxidative stress and inflammation in BV-2 cells. Taken together, engeletin attenuated Aβ1-42-induced oxidative stress and inflammation in BV-2 cells via regulating the of Keap1/Nrf2 pathway. These findings indicated that engeletin might be served as a therapeutic agent for the treatment of AD.
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Affiliation(s)
- Zhixiong Huang
- Department of Neurology, Nanshi Hospital, Nanyang, 473065, China
| | - Hu Ji
- Department of Neurology, Lianshui People's Hospital Affiliated to Kangda College of Nanjing Medical University, Huai'an, 223400, China
| | - Junfeng Shi
- Department of Neurology, Nanshi Hospital, Nanyang, 473065, China
| | - Xinchen Zhu
- Department of Neurology, Nanshi Hospital, Nanyang, 473065, China
| | - Zhongwen Zhi
- Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University, The Second People's Hospital of Huai'an, No. 62 South Huaihai Road, Huai'an, 223002, China.
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19
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Hu XL, Lv XY, Wang R, Long H, Feng JH, Wang BL, Shen W, Liu H, Xiong F, Zhang XQ, Ye WC, Wang H. Optimization of N-Phenylpropenoyl-l-amino Acids as Potent and Selective Inducible Nitric Oxide Synthase Inhibitors for Parkinson's Disease. J Med Chem 2021; 64:7760-7777. [PMID: 34019417 DOI: 10.1021/acs.jmedchem.1c00578] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
N-Phenylpropenoyl-l-amino acids (NPAs) are inducible nitric oxide synthase (iNOS) inhibitors possessing preventive effects for Parkinson's disease (PD). Here, structural modifications for improving the iNOS inhibitory activity and blood-brain barrier (BBB) permeability of NPAs were conducted, leading to 20 optimized NPA derivatives (1-20). Compound 18, with the most potent activity (IC50 = 74 nM), high BBB permeability (Pe = 19.1 × 10-6 cm/s), and high selectivity over other NOS isoforms, was selected as the lead compound. Further studies demonstrated that 18 directly binds to iNOS. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced acute PD model, the oral administration of 18 (1 and 2 mg/kg) exerted preventive effects by alleviating the loss of dopaminergic (DAergic) neurons. Notably, in the MPTP-/probenecid-induced chronic PD model, the same dose of 18 also displayed a therapeutic effect by repairing the damaged DAergic neurons. Finally, good pharmacokinetic properties and low toxicity made 18 a promising candidate for the treatment of PD.
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Affiliation(s)
- Xiao-Long Hu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Xian-Yu Lv
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Rong Wang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Huan Long
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Jia-Hao Feng
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Bao-Lin Wang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Wei Shen
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Hao Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
| | - Fei Xiong
- State Key Laboratory of Bioelectronics, Jiangsu Laboratory for Biomaterials and Devices, Southeast University, Nanjing 210009, People's Republic of China
| | - Xiao-Qi Zhang
- Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632, People's Republic of China
| | - Wen-Cai Ye
- Institute of Traditional Chinese Medicine and Natural Products, Jinan University, Guangzhou 510632, People's Republic of China
| | - Hao Wang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China
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Olivier C, Oliver L, Lalier L, Vallette FM. Drug Resistance in Glioblastoma: The Two Faces of Oxidative Stress. Front Mol Biosci 2021; 7:620677. [PMID: 33585565 PMCID: PMC7873048 DOI: 10.3389/fmolb.2020.620677] [Citation(s) in RCA: 100] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 12/08/2020] [Indexed: 12/26/2022] Open
Abstract
Glioblastomas (GBM) are the most common primary brain tumor with a median survival of 15 months. A population of cells with stem cell properties (glioblastoma stem cells, GSCs) drives the initiation and progression of GBM and is localized in specialized microenvironments which support their behavior. GBM are characterized as extremely resistant to therapy, resulting in tumor recurrence. Reactive oxygen species (ROS) control the cellular stability by influencing different signaling pathways. Normally, redox systems prevent cell oxidative damage; however, in gliomagenesis, the cellular redox mechanisms are highly impaired. Herein we review the dual nature of the redox status in drug resistance. ROS generation in tumor cells affects the cell cycle and is involved in tumor progression and drug resistance in GBM. However, excess ROS production has been found to induce cell death programs such as apoptosis and autophagy. Since GBM cells have a high metabolic rate and produce high levels of ROS, metabolic adaptation in these cells plays an essential role in resistance to oxidative stress-induced cell death. Finally, the microenvironment with the stromal components participates in the enhancement of the oxidative stress to promote tumor progression and drug resistance.
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Affiliation(s)
- Christophe Olivier
- Faculté des Sciences Pharmaceutiques et Biologiques, Nantes, France.,Université de Nantes, INSERM, CRCINA, Nantes, France
| | - Lisa Oliver
- Université de Nantes, INSERM, CRCINA, Nantes, France.,CHU de Nantes, Nantes, France
| | - Lisenn Lalier
- Université de Nantes, INSERM, CRCINA, Nantes, France.,LaBCT, ICO, Saint Herblain, France
| | - François M Vallette
- Université de Nantes, INSERM, CRCINA, Nantes, France.,LaBCT, ICO, Saint Herblain, France
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21
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Sharma A, Muresanu DF, Castellani RJ, Nozari A, Lafuente JV, Sahib S, Tian ZR, Buzoianu AD, Patnaik R, Wiklund L, Sharma HS. Mild traumatic brain injury exacerbates Parkinson's disease induced hemeoxygenase-2 expression and brain pathology: Neuroprotective effects of co-administration of TiO 2 nanowired mesenchymal stem cells and cerebrolysin. PROGRESS IN BRAIN RESEARCH 2020; 258:157-231. [PMID: 33223035 DOI: 10.1016/bs.pbr.2020.09.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Mild traumatic brain injury (mTBI) is one of the leading predisposing factors in the development of Parkinson's disease (PD). Mild or moderate TBI induces rapid production of tau protein and alpha synuclein (ASNC) in the cerebrospinal fluid (CSF) and in several brain areas. Enhanced tau-phosphorylation and ASNC alters the molecular machinery of the brain leading to PD pathology. Recent evidences show upregulation of constitutive isoform of hemeoxygenase (HO-2) in PD patients that correlates well with the brain pathology. mTBI alone induces profound upregulation of HO-2 immunoreactivity. Thus, it would be interesting to explore whether mTBI exacerbates PD pathology in relation to tau, ASNC and HO-2 expression. In addition, whether neurotrophic factors and stem cells known to reduce brain pathology in TBI could induce neuroprotection in PD following mTBI. In this review role of mesenchymal stem cells (MSCs) and cerebrolysin (CBL), a well-balanced composition of several neurotrophic factors and active peptide fragments using nanowired delivery in PD following mTBI is discussed based on our own investigation. Our results show that mTBI induces concussion exacerbates PD pathology and nanowired delivery of MSCs and CBL induces superior neuroprotection. This could be due to reduction in tau, ASNC and HO-2 expression in PD following mTBI, not reported earlier. The functional significance of our findings in relation to clinical strategies is discussed.
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Affiliation(s)
- Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - Rudy J Castellani
- Department of Pathology, University of Maryland, Baltimore, MD, United States
| | - Ala Nozari
- Anesthesiology & Intensive Care, Massachusetts General Hospital, Boston, MA, United States
| | - José Vicente Lafuente
- LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Seaab Sahib
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ranjana Patnaik
- Department of Biomaterials, School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden
| | - Hari Shanker Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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22
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Chen W, Zhao Z, Zhao S, Zhang L, Song Q. Resveratrol and Puerarin loaded polymeric nanoparticles to enhance the chemotherapeutic efficacy in spinal cord injury. Biomed Microdevices 2020; 22:69. [PMID: 32959235 DOI: 10.1007/s10544-020-00521-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/08/2020] [Indexed: 02/07/2023]
Abstract
Spinal cord injury includes inflammation and apoptosis of neurons, which is difficult to cure by systemic drug administration. Administration of natural active compounds (resveratrol and also Puerarin) by advance drug delivery technology improves the patient's conditions. Oil-in-water emulsion method was utilized to prepare resveratrol as well as puerarin loaded PLGA nanoparticles. The nanoparticles were subjected to mean zeta potential, mean particle size, encapsulation efficiency as well as in vitro drug release studies. The biochemical parameters i.e. malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), advanced oxidation products (AOPP), catalase (CAT) and nitrite/nitrate levels were tested for the loaded nanoparticles. Reperfusion injury induced rats treated with 10 mg/kg resveratrol and puerarin loaded nanoparticles protects spine from ischemia injury and supports biological parameters. The mean particle size varies from 238 nm to 274 nm and also particle size distribution was mono-dispersed (0.239 to 0.318). Zeta potential value of nanoparticles was observed to be -12.6 ± 2.1 mV. Optimized nanoparticles reveals 72% -79% of drug release over 36 h by diffusion mechanism. Significantly, lowers the levels of plasma nitrite/nitrate level as well as phosphorylation of p38MAPK pathways in reperfusion injury induced rats. The resveratrol and puerarin loaded nanoparticles decreases free radicals produced by reperfusion injury induced rats, as well as decrease of oxidative stress because of IRI. Resveratrol and puerarin loaded nanoparticles decreases GSH, SOD and CAT antioxidant level, which helps in overall health improvement of patients.
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Affiliation(s)
- Wei Chen
- Department of Neurosurgery, Linyi central hospital, Yishui county, Linyi, 276400, Shandong province, China
| | - Zongqin Zhao
- Department of pathology, Qingdao Hiser Hospital, Qingdao, 266033, Shandong, China
| | - Shuchao Zhao
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong Province, China
| | - Lizhong Zhang
- Department of pathology, Linyi People's Hospital, Linyi, 276003, Shandong Province, China
| | - Qimin Song
- Department of Neurosurgery, Linyi People's Hospital, Linyi, 276003, Shandong province, China.
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23
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Effects of circulating extracellular microvesicles from spinal cord-injured adults on endothelial cell function. Clin Sci (Lond) 2020; 134:777-789. [PMID: 32219341 DOI: 10.1042/cs20200047] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 03/25/2020] [Accepted: 03/26/2020] [Indexed: 12/15/2022]
Abstract
People with spinal cord injury (SCI) have three- to four-fold greater risk of cardiovascular disease (CVD) compared with those without SCI. Although circulating extracellular microvesicles are key effectors of vascular health and disease, how their functional phenotype might be altered with SCI is unknown. The aim of the present study was to determine the effects of microvesicles isolated from SCI adults on endothelial cell inflammation and oxidative stress as well as endothelial nitric oxide (NO) synthase (eNOS) activation and tissue-type plasminogen activator (t-PA) expression. Eighteen young and middle-aged adults were studied: 10 uninjured (7M/3F; age: 39 ± 3 years) and 8 cervical level spinal cord injured (SCI; 7M/1F; 46 ± 4 years; cervical injury: C3: n=1; C5: n=4; C6: n=3). Circulating microvesicles were isolated, enumerated and collected from plasma by flow cytometry. Human umbilical vein endothelial cells (HUVECs) were cultured and treated with microvesicles from either the uninjured or SCI adults. Microvesicles from SCI adults did not affect cellular markers or mediators of inflammation and oxidative stress. However, microvesicles from the SCI adults significantly blunted eNOS activation, NO bioavailability and t-PA production. Intercellular expression of phosphorylated eNOS at Ser1177 and Thr495 sites, specifically, were ∼65% lower and ∼85% higher, respectively, in cells treated with microvesicles from SCI compared with uninjured adults. Decreased eNOS activity and NO production as well as impaired t-PA bioavailability renders the vascular endothelium highly susceptible to atherosclerosis and thrombosis. Thus, circulating microvesicles may contribute to the increased risk of vascular disease and thrombotic events associated with SCI.
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24
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Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Investigating the ameliorative effect of alpha-mangostin on development and existing pain in a rat model of neuropathic pain. Phytother Res 2020; 34:3211-3225. [PMID: 32592535 DOI: 10.1002/ptr.6768] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 05/17/2020] [Accepted: 05/24/2020] [Indexed: 01/01/2023]
Abstract
Mangosteen fruit has been used for various disorders, including pain. The effects of alpha-mangostin, the main component of mangosteen, on the neuropathic pain caused by chronic constriction injury (CCI) were evaluated in rats. In treatment groups, alpha-mangostin (10, 50, 100 mg/kg/day, i.p.) was administered from Day 0, the day of surgery, for 14 days. The degree of heat hyperalgesia, cold, and mechanical allodynia was assessed on Days 0, 3, 5, 7, 10, and 14. The lumbar spinal cord levels of MDA, GSH, inflammatory markers (TLR-4, TNF-α, MMP2, COX2, IL-1β, iNOS, and NO), apoptotic markers (Bcl-2, Bax, and caspase-3) were measured by western blot on Days 7 and 14. Rats in the CCI group showed thermal hyperalgesia, cold, and mechanical allodynia on Days 3-14. All concentrations of alpha-mangostin alleviated CCI-induced behavioral alterations. MDA level augmented and GSH level decreased in the CCI group and alpha-mangostin (50, 100 mg/kg) reversed the alterations. An enhancement in the levels of all inflammatory markers, Bax, and caspase-3 was shown on Days 7 and 14, which was controlled by alpha-mangostin (50 mg/kg). The detected antinociceptive effects of alpha-mangostin may be mediated through antioxidant, anti-inflammatory, and antiapoptotic properties.
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Affiliation(s)
| | - Bibi Marjan Razavi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.,Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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25
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Vismara I, Papa S, Veneruso V, Mauri E, Mariani A, De Paola M, Affatato R, Rossetti A, Sponchioni M, Moscatelli D, Sacchetti A, Rossi F, Forloni G, Veglianese P. Selective Modulation of A1 Astrocytes by Drug-Loaded Nano-Structured Gel in Spinal Cord Injury. ACS NANO 2020; 14:360-371. [PMID: 31887011 DOI: 10.1021/acsnano.9b05579] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Astrogliosis has a very dynamic response during the progression of spinal cord injury, with beneficial or detrimental effects on recovery. It is therefore important to develop strategies to target activated astrocytes and their harmful molecular mechanisms so as to promote a protective environment to counteract the progression of the secondary injury. The challenge is to formulate an effective therapy with maximum protective effects, but reduced side effects. In this study, a functionalized nanogel-based nanovector was selectively internalized in activated mouse or human astrocytes. Rolipram, an anti-inflammatory drug, when administered by these nanovectors limited the inflammatory response in A1 astrocytes, reducing iNOS and Lcn2, which in turn reverses the toxic effect of proinflammatory astrocytes on motor neurons in vitro, showing advantages over conventionally administered anti-inflammatory therapy. When tested acutely in a spinal cord injury mouse model, it improved motor performance, but only in the early stage after injury, reducing the astrocytosis and preserving neuronal cells.
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Affiliation(s)
- Irma Vismara
- Department of Neuroscience , Istituto di Ricerche Farmacologiche Mario Negri IRCCS , via Mario Negri 2 , 20156 Milano , Italy
| | - Simonetta Papa
- Department of Neuroscience , Istituto di Ricerche Farmacologiche Mario Negri IRCCS , via Mario Negri 2 , 20156 Milano , Italy
| | - Valeria Veneruso
- Department of Neuroscience , Istituto di Ricerche Farmacologiche Mario Negri IRCCS , via Mario Negri 2 , 20156 Milano , Italy
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta" , Politecnico di Milano , via Mancinelli 7 , 20131 Milano , Italy
| | - Emanuele Mauri
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta" , Politecnico di Milano , via Mancinelli 7 , 20131 Milano , Italy
| | - Alessandro Mariani
- Department of Environmental Health Sciences , Istituto di Ricerche Farmacologiche Mario Negri IRCCS , via Mario Negri 2 , 20156 Milan , Italy
| | - Massimiliano De Paola
- Department of Environmental Health Sciences , Istituto di Ricerche Farmacologiche Mario Negri IRCCS , via Mario Negri 2 , 20156 Milan , Italy
| | - Roberta Affatato
- Department of Oncology , Istituto di Ricerche Farmacologiche Mario Negri IRCCS , via Mario Negri 2 , 20156 Milan , Italy
| | - Arianna Rossetti
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta" , Politecnico di Milano , via Mancinelli 7 , 20131 Milano , Italy
| | - Mattia Sponchioni
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta" , Politecnico di Milano , via Mancinelli 7 , 20131 Milano , Italy
| | - Davide Moscatelli
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta" , Politecnico di Milano , via Mancinelli 7 , 20131 Milano , Italy
| | - Alessandro Sacchetti
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta" , Politecnico di Milano , via Mancinelli 7 , 20131 Milano , Italy
| | - Filippo Rossi
- Department of Chemistry, Materials and Chemical Engineering "Giulio Natta" , Politecnico di Milano , via Mancinelli 7 , 20131 Milano , Italy
| | - Gianluigi Forloni
- Department of Neuroscience , Istituto di Ricerche Farmacologiche Mario Negri IRCCS , via Mario Negri 2 , 20156 Milano , Italy
| | - Pietro Veglianese
- Department of Neuroscience , Istituto di Ricerche Farmacologiche Mario Negri IRCCS , via Mario Negri 2 , 20156 Milano , Italy
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26
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Kuffler DP. Injury-Induced Effectors of Neuropathic Pain. Mol Neurobiol 2019; 57:51-66. [PMID: 31701439 DOI: 10.1007/s12035-019-01756-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 08/29/2019] [Indexed: 02/07/2023]
Abstract
Injuries typically result in the development of neuropathic pain, which decreases in parallel with wound healing. However, the pain may remain after the injury appears to have healed, which is generally associated with an ongoing underlying pro-inflammatory state. Injury induces many cells to release factors that contribute to the development of a pro-inflammatory state, which is considered an essential first step towards wound healing. However, pain elimination requires a transition of the injury site from pro- to anti-inflammatory. Therefore, developing techniques that eliminate chronic pain require an understanding of the cells resident at and recruited to injury sites, the factors they release, that promote a pro-inflammatory state, and promote the subsequent transition of that site to be anti-inflammatory. Although a relatively large number of cells, factors, and gene expression changes are involved in these processes, it may be possible to control a relatively small number of them leading to the reduction and elimination of chronic neuropathic pain. This first of two papers examines the roles of the most salient cells and mediators associated with the development and maintenance of chronic neuropathic pain. The following paper examines the cells and mediators involved in reducing and eliminating chronic neuropathic pain.
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Affiliation(s)
- Damien P Kuffler
- Institute of Neurobiology, Medical Sciences Campus, University of Puerto Rico, 201 Blvd. del Valle, San Juan, PR, 00901, USA.
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27
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Choi SR, Beitz AJ, Lee JH. Spinal Nitric Oxide Synthase Type II Increases Neurosteroid-metabolizing Cytochrome P450c17 Expression in a Rodent Model of Neuropathic Pain. Exp Neurobiol 2019; 28:516-528. [PMID: 31495080 PMCID: PMC6751860 DOI: 10.5607/en.2019.28.4.516] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 06/07/2019] [Accepted: 07/08/2019] [Indexed: 11/29/2022] Open
Abstract
We have previously demonstrated that the neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces functional potentiation of N-methyl-D-aspartate (NMDA) receptors via increases in phosphorylation of NMDA receptor GluN1 subunit (pGluN1). However, the modulatory mechanisms responsible for the expression of the DHEA-synthesizing enzyme, cytochrome P450c17 following peripheral nerve injury have yet to be examined. Here we determined whether oxidative stress induced by the spinal activation of nitric oxide synthase type II (NOS-II) modulates the expression of P450c17 and whether this process contributes to the development of neuropathic pain in rats. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of NOS-II in microglial cells and NO levels in the lumbar spinal cord dorsal horn at postoperative day 5. Intrathecal administration of the NOS-II inhibitor, L-NIL during the induction phase of neuropathic pain (postoperative days 0~5) significantly reduced the CCI-induced development of mechanical allodynia and thermal hyperalgesia. Sciatic nerve injury increased the expression of PKC- and PKA-dependent pGluN1 as well as the mRNA and protein levels of P450c17 in the spinal cord at postoperative day 5, and these increases were suppressed by repeated administration of L-NIL. Co-administration of DHEAS together with L-NIL restored the development of neuropathic pain and pGluN1 that were originally inhibited by L-NIL administration alone. Collectively these results provide strong support for the hypothesis that activation of NOS-II increases the mRNA and protein levels of P450c17 in the spinal cord, ultimately leading to the development of central sensitization and neuropathic pain induced by peripheral nerve injury.
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Affiliation(s)
- Sheu-Ran Choi
- Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Alvin J Beitz
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA
| | - Jang-Hern Lee
- Department of Veterinary Physiology, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
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28
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Combining molecular intervention with in vivo imaging to untangle mechanisms of axon pathology and outgrowth following spinal cord injury. Exp Neurol 2019; 318:1-11. [DOI: 10.1016/j.expneurol.2019.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 03/20/2019] [Accepted: 04/07/2019] [Indexed: 12/17/2022]
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29
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Polydatin alleviates traumatic spinal cord injury by reducing microglial inflammation via regulation of iNOS and NLRP3 inflammasome pathway. Int Immunopharmacol 2019; 70:28-36. [DOI: 10.1016/j.intimp.2019.02.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 01/08/2019] [Accepted: 02/04/2019] [Indexed: 01/30/2023]
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30
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Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury. Exp Neurol 2018; 311:115-124. [PMID: 30268767 DOI: 10.1016/j.expneurol.2018.09.018] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/07/2018] [Accepted: 09/27/2018] [Indexed: 11/24/2022]
Abstract
In humans, spinal cord injury (SCI) is often accompanied by additional tissue damage (polytrauma) that can engage pain (nociceptive) fibers. Prior work has shown that this nociceptive input can expand the area of tissue damage (secondary injury), undermine behavioral recovery, and enhance the development of chronic pain. Here, it is shown that nociceptive input given a day after a lower thoracic contusion injury in rats enhances the infiltration of red blood cells at the site of injury, producing an area of hemorrhage that expands secondary injury. Peripheral nociceptive fibers were engaged 24 h after injury by means of electrical stimulation (shock) applied at an intensity that engages unmyelinated pain (C) fibers or through the application of the irritant capsaicin. Convergent western immunoblot and cyanmethemoglobin colorimetric assays showed that both forms of stimulation increased the concentration of hemoglobin at the site of injury, with a robust effect observed 3-24 h after stimulation. Histopathology confirmed that shock treatment increased the area of hemorrhage and the infiltration of red blood cells. SCI can lead to hemorrhage by engaging the sulfonylurea receptor 1 (SUR1) transient receptor potential melastatin 4 (TRPM4) channel complex in neurovascular endothelial cells, which leads to cell death and capillary fragmentation. Histopathology confirmed that areas of hemorrhage showed capillary fragmentation. Co-immunoprecipitation of the SUR1-TRPM4 complex showed that it was up-regulated by noxious stimulation. Shock-induced hemorrhage was associated with an acute disruption in locomotor performance. These results imply that noxious stimulation impairs long-term recovery because it amplifies the breakdown of the blood spinal cord barrier (BSCB) and the infiltration of red blood cells, which expands the area of secondary injury.
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31
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Staunton CA, Barrett-Jolley R, Djouhri L, Thippeswamy T. Inducible nitric oxide synthase inhibition by 1400W limits pain hypersensitivity in a neuropathic pain rat model. Exp Physiol 2018; 103:535-544. [PMID: 29441689 DOI: 10.1113/ep086764] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 02/08/2018] [Indexed: 11/08/2022]
Abstract
NEW FINDINGS What is the central question of this study? Can modulation of inducible NO synthase reduce pain behaviour and pro-inflammatory cytokine signalling in a rat model of neuropathic pain? What is the main finding and its importance? Nitric oxide synthase-based therapies could be effective for the treatment of peripheral neuropathic pain. ABSTRACT Peripheral neuropathic pain (PNP), resulting from injury to or dysfunction of a peripheral nerve, is a major health problem that affects 7-8% of the population. It is inadequately controlled by current drugs and is characterized by pain hypersensitivity, which is believed to be attributable to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: (i) whether reducing levels of nitric oxide (NO) with 1400W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent or attenuate pain hypersensitivity; and (ii) the effects of 1400W on plasma concentrations of several cytokines that are secreted after iNOS upregulation during chronic pain states. The L5 spinal nerve axotomy (SNA) model of PNP was used, and 1400W (20 mg kg-1 ) was administered i.p. at 8 h intervals for 3 days starting at 18 h post-SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400W were examined using multiplex enzyme-linked immunosorbent assay. The SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400W significantly: (i) limited development of mechanical hypersensitivity at 66 h post-SNA and of heat hypersensitivity at 42 h and at several time points tested thereafter; and (ii) increased the plasma concentrations of interleukin (IL)-1α, IL-1β and IL-10 in the SNA rats. The findings suggest that 1400W might exert its analgesic effects by reducing iNOS and altering the balance between the pro-inflammatory (IL-1β and IL-1α) and anti-inflammatory (IL-10) cytokines and that therapies targeting NO or its enzymes might be effective for the treatment of PNP.
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Affiliation(s)
- C A Staunton
- Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
| | - R Barrett-Jolley
- Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK
| | - L Djouhri
- Department of Physiology, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - T Thippeswamy
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
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32
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Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:3804979. [PMID: 29770166 PMCID: PMC5892600 DOI: 10.1155/2018/3804979] [Citation(s) in RCA: 320] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 12/07/2017] [Indexed: 12/16/2022]
Abstract
Acute ischemic stroke is a common cause of morbidity and mortality worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes. Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury) has been found to play a key role in the process. Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death. Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier. In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage. This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage.
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Ma YH, Zeng X, Qiu XC, Wei QS, Che MT, Ding Y, Liu Z, Wu GH, Sun JH, Pang M, Rong LM, Liu B, Aljuboori Z, Han I, Ling EA, Zeng YS. Perineurium-like sheath derived from long-term surviving mesenchymal stem cells confers nerve protection to the injured spinal cord. Biomaterials 2018; 160:37-55. [PMID: 29353106 DOI: 10.1016/j.biomaterials.2018.01.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 01/08/2018] [Accepted: 01/10/2018] [Indexed: 01/01/2023]
Abstract
The functional multipotency enables mesenchymal stem cells (MSCs) promising translational potentials in treating spinal cord injury (SCI). Yet the fate of MSCs grafted into the injured spinal cord has not been fully elucidated even in preclinical studies, rendering concerns of their safety and genuine efficacy. Here we used a rat spinal cord transection model to evaluate the cell fate of allograft bone marrow derived MSCs. With the application of immunosuppressant, donor cells, delivered by biocompatible scaffold, survived up to 8 weeks post-grafting. Discernible tubes formed by MSCs were observed beginning 2 weeks after transplantation and they dominated the morphological features of implanted MSCs at 8 weeks post-grafting. The results of immunocytochemistry and transmission electron microscopy displayed the formation of perineurium-like sheath by donor cells, which, in a manner comparable to the perineurium in peripheral nerve, enwrapped host myelins and axons. The MSC-derived perineurium-like sheath secreted a group of trophic factors and permissive extracellular matrix, and served as a physical and chemical barrier to insulate the inner nerve fibers from ambient oxidative insults by the secretion of soluble antioxidant, superoxide dismutase-3 (SOD3). As a result, many intact regenerating axons were preserved in the injury/graft site following the forming of perineurium-like sheath. A parallel study utilizing a good manufacturing practice (GMP) grade human umbilical cord-derived MSCs or allogenic MSCs in an acute contusive/compressive SCI model exhibited a similar perineurium-like sheath formed by surviving donor cells in rat spinal cord at 3 weeks post-grafting. The present study for the first time provides an unambiguous morphological evidence of perineurium-like sheath formed by transplanted MSCs and a novel therapeutic mechanism of MSCs in treating SCI.
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Affiliation(s)
- Yuan-Huan Ma
- Guangdong Key Laboratory of Age-Related Cardiocerebral Diseases, Institute of Neurology, Guangdong Medical University, Zhanjiang, Guangdong Province, 524023, China; Department of Histology and Embryology, Guangdong Medical University, Zhanjiang, Guangdong Province, 524023, China; Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China
| | - Xiang Zeng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China.
| | - Xue-Cheng Qiu
- Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China
| | - Qing-Shuai Wei
- Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China
| | - Ming-Tian Che
- Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China
| | - Ying Ding
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China
| | - Zhou Liu
- Guangdong Key Laboratory of Age-Related Cardiocerebral Diseases, Institute of Neurology, Guangdong Medical University, Zhanjiang, Guangdong Province, 524023, China; Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China
| | - Guo-Hui Wu
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China
| | - Jia-Hui Sun
- Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China
| | - Mao Pang
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510630, China
| | - Li-Min Rong
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510630, China
| | - Bin Liu
- Department of Spine Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510630, China
| | - Zaid Aljuboori
- Department of Neurosurgery, University of Louisville, Louisville, KY 40292, USA
| | - Inbo Han
- Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea
| | - Eng-Ang Ling
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Yuan-Shan Zeng
- Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, China; Key Laboratory for Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong, 510080, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
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Lei Y. Myricitrin decreases traumatic injury of the spinal cord and exhibits antioxidant and anti-inflammatory activities in a rat model via inhibition of COX-2, TGF-β1, p53 and elevation of Bcl-2/Bax signaling pathway. Mol Med Rep 2017; 16:7699-7705. [DOI: 10.3892/mmr.2017.7567] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 03/21/2017] [Indexed: 11/05/2022] Open
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Real CC, Garcia PC, Britto LRG. Treadmill Exercise Prevents Increase of Neuroinflammation Markers Involved in the Dopaminergic Damage of the 6-OHDA Parkinson’s Disease Model. J Mol Neurosci 2017; 63:36-49. [DOI: 10.1007/s12031-017-0955-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 07/21/2017] [Indexed: 12/21/2022]
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Alizadeh A, Dyck SM, Kataria H, Shahriary GM, Nguyen DH, Santhosh KT, Karimi-Abdolrezaee S. Neuregulin-1 positively modulates glial response and improves neurological recovery following traumatic spinal cord injury. Glia 2017; 65:1152-1175. [DOI: 10.1002/glia.23150] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 03/12/2017] [Accepted: 03/22/2017] [Indexed: 12/29/2022]
Affiliation(s)
- Arsalan Alizadeh
- Regenerative Medicine Program, Department of Physiology and Pathophysiology; Spinal Cord Research Centre, University of Manitoba; Winnipeg Manitoba R3E 0J9 Canada
| | - Scott M. Dyck
- Regenerative Medicine Program, Department of Physiology and Pathophysiology; Spinal Cord Research Centre, University of Manitoba; Winnipeg Manitoba R3E 0J9 Canada
| | - Hardeep Kataria
- Regenerative Medicine Program, Department of Physiology and Pathophysiology; Spinal Cord Research Centre, University of Manitoba; Winnipeg Manitoba R3E 0J9 Canada
| | - Ghazaleh M. Shahriary
- Regenerative Medicine Program, Department of Physiology and Pathophysiology; Spinal Cord Research Centre, University of Manitoba; Winnipeg Manitoba R3E 0J9 Canada
| | - Dung H. Nguyen
- Regenerative Medicine Program, Department of Physiology and Pathophysiology; Spinal Cord Research Centre, University of Manitoba; Winnipeg Manitoba R3E 0J9 Canada
| | - Kallivalappil T. Santhosh
- Regenerative Medicine Program, Department of Physiology and Pathophysiology; Spinal Cord Research Centre, University of Manitoba; Winnipeg Manitoba R3E 0J9 Canada
| | - Soheila Karimi-Abdolrezaee
- Regenerative Medicine Program, Department of Physiology and Pathophysiology; Spinal Cord Research Centre, University of Manitoba; Winnipeg Manitoba R3E 0J9 Canada
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Zhou W, Yuan T, Gao Y, Yin P, Liu W, Pan C, Liu Y, Yu X. IL-1β-induces NF-κB and upregulates microRNA-372 to inhibit spinal cord injury recovery. J Neurophysiol 2017; 117:2282-2291. [PMID: 28298306 DOI: 10.1152/jn.00936.2016] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/27/2017] [Accepted: 03/10/2017] [Indexed: 12/14/2022] Open
Abstract
Excessive inflammation including IL-1β-initiated signaling is among the earlies reactions that can cause neuronal damage following spinal cord injury (SCI). It has been suggested that microRNAs may participate in stem cell repair to facilitate functional recovery following SCI. In this study we have shown that in cultured human neural stem cells (hNSC), IL-1β reduced the expression of both KIF3B (kinesin family member 3B) and NOSIP (nitric oxide synthase-interacting protein), two key modulators for restricting inflammation and promoting neuronal regeneration. The induction of microRNA-372 (miR-372) by IL-1β is specifically responsible for the inhibition of KIF3B and NOSIP. The 3'-untranslated regions (UTRs) of both KIF3B and NOSIP contain targeting sequences to miR-372 that directly inhibit their expression. Moreover, we found that the expression of miR-372 was stimulated in hNSC by IL-1β through an NF-κB binding site at its promoter region. Finally, stable overexpression of miR-372 inhibitor in hNSC rescued the IL-1β-induced impairment as shown by significant improvements in tissue water content, myeloperoxidase activity, and behavioral assessments in SCI rats. These findings suggest a critical role of miR-372 in inflammatory signaling and pinpoint a novel target for the treatment of acute SCI.NEW & NOTEWORTHY Our data demonstrate that IL-1β can impair the functional recovery of neural stem cell transplant therapy for spinal cord injury (SCI) treatment in rats. This effect is dependent on microRNA-372 (miR-372)-dependent gene repression of KIF3B and NOSIP. Therefore, specific knockdown of miR-372 may provide benefits for SCI treatments.
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Affiliation(s)
- Wei Zhou
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital East Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, People's Republic of China.,Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China; and
| | - Tongzhou Yuan
- Department of Orthopaedic Surgery, Second Affiliated Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Youshui Gao
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China; and
| | - Peipei Yin
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China; and
| | - Wei Liu
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China; and
| | - Chenhao Pan
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China; and
| | - Yingjie Liu
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China; and
| | - Xiaowei Yu
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital East Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, People's Republic of China; .,Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, People's Republic of China; and
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Maggio DM, Singh A, Iorgulescu JB, Bleicher DH, Ghosh M, Lopez MM, Tuesta LM, Flora G, Dietrich WD, Pearse DD. Identifying the Long-Term Role of Inducible Nitric Oxide Synthase after Contusive Spinal Cord Injury Using a Transgenic Mouse Model. Int J Mol Sci 2017; 18:ijms18020245. [PMID: 28125047 PMCID: PMC5343782 DOI: 10.3390/ijms18020245] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/05/2017] [Accepted: 01/15/2017] [Indexed: 02/07/2023] Open
Abstract
Inducible nitric oxide synthase (iNOS) is a potent mediator of oxidative stress during neuroinflammation triggered by neurotrauma or neurodegeneration. We previously demonstrated that acute iNOS inhibition attenuated iNOS levels and promoted neuroprotection and functional recovery after spinal cord injury (SCI). The present study investigated the effects of chronic iNOS ablation after SCI using inos-null mice. iNOS-/- knockout and wild-type (WT) control mice underwent a moderate thoracic (T8) contusive SCI. Locomotor function was assessed weekly, using the Basso Mouse Scale (BMS), and at the endpoint (six weeks), by footprint analysis. At the endpoint, the volume of preserved white and gray matter, as well as the number of dorsal column axons and perilesional blood vessels rostral to the injury, were quantified. At weeks two and three after SCI, iNOS-/- mice exhibited a significant locomotor improvement compared to WT controls, although a sustained improvement was not observed during later weeks. At the endpoint, iNOS-/- mice showed significantly less preserved white and gray matter, as well as fewer dorsal column axons and perilesional blood vessels, compared to WT controls. While short-term antagonism of iNOS provides histological and functional benefits, its long-term ablation after SCI may be deleterious, blocking protective or reparative processes important for angiogenesis and tissue preservation.
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Affiliation(s)
- Dominic M Maggio
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Neurological Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institute of Heath, Bethesda, MD 20824, USA.
| | - Amanpreet Singh
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - J Bryan Iorgulescu
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
| | - Drew H Bleicher
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Mousumi Ghosh
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Michael M Lopez
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Luis M Tuesta
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
| | - Govinder Flora
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - W Dalton Dietrich
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Damien D Pearse
- The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- The Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
- Bruce W. Carter Department of Veterans Affairs Medical Center, Miami, FL 33136, USA.
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Low-Level Laser Irradiation Improves Motor Recovery After Contusive Spinal Cord Injury in Rats. Tissue Eng Regen Med 2017; 14:57-64. [PMID: 30603462 DOI: 10.1007/s13770-016-0003-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 04/07/2016] [Accepted: 05/03/2016] [Indexed: 10/20/2022] Open
Abstract
This study investigated the therapeutic effects of low-level laser irradiation (LLLI) on the recovery of motor function and its underlying mechanisms in rats with spinal cord injury (SCI). The spinal cord was contused at the T11 level using a New York University impactor. Thirty-eight rats were randomly divided into four groups: LLLI with 0.08 J, 0.4 J, 0.8 J, and sham. We transcutaneously applied at the lesion site of the spinal contusive rats 5 min after injury and then daily for 21 days. The Basso, Beattie and Bresnahan (BBB) locomotor scale and combined behavioral score (CBS) were used to evaluate motor function. The spinal segments of rostral and caudal from the lesion site, the epicenter, and L4-5 were collected from normal and the all groups at 7 days after SCI. The expression of tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) was compared across groups in all regions. In the present study, LLLI with 0.4 J and 0.8 J led to a significant improvement in motor function compared to sham LLLI, which significantly decreased TNF-α expression at the lesion epicenter and reduced iNOS expression in the caudal segment for all LLLI groups and in the L4-5 segments for the 0.4 J and 0.8 J groups when compared to sham LLLI group. Our results demonstrate that transcutaneous LLLI modulate inflammatory mediators to enhance motor function recovery after SCI. Thus, LLLI in acute phase after SCI might have therapeutic potential for neuroprotection and restoration of motor function following SCI.
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Kim DK, Kweon KJ, Kim P, Kim HJ, Kim SS, Sohn NW, Maeng S, Shin JW. Ginsenoside Rg3 Improves Recovery from Spinal Cord Injury in Rats via Suppression of Neuronal Apoptosis, Pro-Inflammatory Mediators, and Microglial Activation. Molecules 2017; 22:molecules22010122. [PMID: 28085110 PMCID: PMC6155773 DOI: 10.3390/molecules22010122] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 01/03/2017] [Accepted: 01/09/2017] [Indexed: 12/04/2022] Open
Abstract
Spinal cord injury (SCI) is one of the most devastating medical conditions; however, currently, there are no effective pharmacological interventions for SCI. Ginsenoside Rg3 (GRg3) is one of the protopanaxadiols that show anti-inflammatory, anti-oxidant, and neuroprotective effects. The present study investigated the neuroprotective effect of GRg3 following SCI in rats. SCI was induced using a static compression model at vertebral thoracic level 10 for 5 min. GRg3 was administrated orally at a dose of 10 or 30 mg/kg/day for 14 days after the SCI. GRg3 (30 mg/kg) treatment markedly improved behavioral motor functions, restored lesion size, preserved motor neurons in the spinal tissue, reduced Bax expression and number of TUNEL-positive cells, and suppressed mRNA expression of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. GRg3 also attenuated the over-production of cyclooxygenase-2 and inducible nitric oxide synthase after SCI. Moreover, GRg3 markedly suppressed microglial activation in the spinal tissue. In conclusion, GRg3 treatment led to a remarkable recovery of motor function and a reduction in spinal tissue damage by suppressing neuronal apoptosis and inflammatory responses after SCI. These results suggest that GRg3 may be a potential therapeutic agent for the treatment of SCI.
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Affiliation(s)
- Dong-Kyu Kim
- Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17404, Korea.
| | - Ki-Jung Kweon
- Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17404, Korea.
| | - Pyungsoo Kim
- Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17404, Korea.
| | - Hee-Jung Kim
- Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17404, Korea.
| | - Sung-Soo Kim
- Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17404, Korea.
| | - Nak-Won Sohn
- Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17404, Korea.
| | - Sungho Maeng
- Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17404, Korea.
| | - Jung-Won Shin
- Department of East-West Medical Science, Graduate School of East-West Medical Science, Kyung Hee University, Yongin 17404, Korea.
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Shultz RB, Zhong Y. Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury. Neural Regen Res 2017; 12:702-713. [PMID: 28616020 PMCID: PMC5461601 DOI: 10.4103/1673-5374.206633] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Minocycline hydrochloride (MH), a semi-synthetic tetracycline derivative, is a clinically available antibiotic and anti-inflammatory drug that also exhibits potent neuroprotective activities. It has been shown to target multiple secondary injury mechanisms in spinal cord injury, via its anti-inflammatory, anti-oxidant, and anti-apoptotic properties. The secondary injury mechanisms that MH can potentially target include inflammation, free radicals and oxidative stress, glutamate excitotoxicity, calcium influx, mitochondrial dysfunction, ischemia, hemorrhage, and edema. This review discusses the potential mechanisms of the multifaceted actions of MH. Its anti-inflammatory and neuroprotective effects are partially achieved through conserved mechanisms such as modulation of p38 mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways as well as inhibition of matrix metalloproteinases (MMPs). Additionally, MH can directly inhibit calcium influx through the N-methyl-D-aspartate (NMDA) receptors, mitochondrial calcium uptake, poly(ADP-ribose) polymerase-1 (PARP-1) enzymatic activity, and iron toxicity. It can also directly scavenge free radicals. Because it can target many secondary injury mechanisms, MH treatment holds great promise for reducing tissue damage and promoting functional recovery following spinal cord injury.
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Affiliation(s)
- Robert B Shultz
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
| | - Yinghui Zhong
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
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Narin F, Hanalioglu S, Ustun H, Kilinc K, Bilginer B. Topiramate as a neuroprotective agent in a rat model of spinal cord injury. Neural Regen Res 2017; 12:2071-2076. [PMID: 29323048 PMCID: PMC5784357 DOI: 10.4103/1673-5374.221164] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Topiramate (TPM) is a widely used antiepileptic and antimigraine agent which has been shown to exert neuroprotective effects in various experimental traumatic brain injury and stroke models. However, its utility in spinal cord injury has not been studied extensively. Thus, we evaluated effects of TPM on secondary cellular injury mechanisms in an experimental rat model of traumatic spinal cord injury (SCI). After rat models of thoracic contusive SCI were established by free weight-drop method, TPM (40 mg/kg) was given at 12-hour intervals for four times orally. Post TPM treatment, malondialdehyde and protein carbonyl levels were significantly reduced and reduced glutathione levels were increased, while immunoreactivity for endothelial nitric oxide synthase, inducible nitric oxide synthase, and apoptotic peptidase activating factor 1 was diminished in SCI rats. In addition, TPM treatment improved the functional recovery of SCI rats. This study suggests that administration of TPM exerts neuroprotective effects on SCI.
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Affiliation(s)
- Firat Narin
- Department of Neurosurgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Sahin Hanalioglu
- Department of Neurosurgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Huseyin Ustun
- Department of Pathology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Kamer Kilinc
- Department of Biochemistry, TOBB University of Economics and Technology Faculty of Medicine, Ankara, Turkey
| | - Burcak Bilginer
- Department of Neurosurgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
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Wu Y, Streijger F, Wang Y, Lin G, Christie S, Mac-Thiong JM, Parent S, Bailey CS, Paquette S, Boyd MC, Ailon T, Street J, Fisher CG, Dvorak MF, Kwon BK, Li L. Parallel Metabolomic Profiling of Cerebrospinal Fluid and Serum for Identifying Biomarkers of Injury Severity after Acute Human Spinal Cord Injury. Sci Rep 2016; 6:38718. [PMID: 27966539 PMCID: PMC5155264 DOI: 10.1038/srep38718] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 11/10/2016] [Indexed: 12/28/2022] Open
Abstract
Suffering an acute spinal cord injury (SCI) can result in catastrophic physical and emotional loss. Efforts to translate novel therapies in acute clinical trials are impeded by the SCI community's singular dependence upon functional outcome measures. Therefore, a compelling rationale exists to establish neurochemical biomarkers for the objective classification of injury severity. In this study, CSF and serum samples were obtained at 3 time points (~24, 48, and 72 hours post-injury) from 30 acute SCI patients (10 AIS A, 12 AIS B, and 8 AIS C). A differential chemical isotope labeling liquid chromatography mass spectrometry (CIL LC-MS) with a universal metabolome standard (UMS) was applied to the metabolomic profiling of these samples. This method provided enhanced detection of the amine- and phenol-containing submetabolome. Metabolic pathway analysis revealed dysregulations in arginine-proline metabolism following SCI. Six CSF metabolites were identified as potential biomarkers of baseline injury severity, and good classification performance (AUC > 0.869) was achieved by using combinations of these metabolites in pair-wise comparisons of AIS A, B and C patients. Using the UMS strategy, the current data set can be expanded to a larger cohort for biomarker validation, as well as discovering biomarkers for predicting neurologic outcome.
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Affiliation(s)
- Yiman Wu
- Department of Chemistry, University of Alberta, Edmonton, AB, T6G2G2, Canada
| | - Femke Streijger
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - Yining Wang
- Department of Computing Science, University of Alberta, Edmonton, AB, T6T 2E8, Canada
| | - Guohui Lin
- Department of Computing Science, University of Alberta, Edmonton, AB, T6T 2E8, Canada
| | - Sean Christie
- Division of Neurosurgery, Dalhousie University, Halifax Infirmary, 1796 Summer Street, Halifax, NS, B3H 3A7, Canada
| | - Jean-Marc Mac-Thiong
- Hôpital du Sacré-Coeur de Montréal, 5400 Boul Gouin O, Montréal, QC, H4J 1C5, Canada
| | - Stefan Parent
- Chu Sainte-Justine, Dept. of Surgery, Université de Montréal, PO Box 6128, Station Centre-ville, Montreal, QC, H3C 3J7, Canada
| | - Christopher S Bailey
- Division of Orthopaedic Surgery, Schulich Medicine &Dentistry, Victoria Hospital 800 Commissioners Road East, Room E4 120, London, ON, N6C 5W9, Canada
| | - Scott Paquette
- Division of Neurosurgery, University of British Columbia, Vancouver Spine Surgery Institute, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - Michael C Boyd
- Division of Neurosurgery, University of British Columbia, Vancouver Spine Surgery Institute, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - Tamir Ailon
- Division of Neurosurgery, University of British Columbia, Vancouver Spine Surgery Institute, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - John Street
- Department of Orthopaedics, University of British Columbia, Vancouver Spine Surgery Institute, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - Charles G Fisher
- Department of Orthopaedics, University of British Columbia, Vancouver Spine Surgery Institute, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - Marcel F Dvorak
- Department of Orthopaedics, University of British Columbia, Vancouver Spine Surgery Institute, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - Brian K Kwon
- International Collaboration on Repair Discoveries (ICORD), University of British Columbia, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada
| | - Liang Li
- Department of Chemistry, University of Alberta, Edmonton, AB, T6G2G2, Canada
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Hosseini M, Rajaei Z, Alaei H, Tajadini M. The Effects of Crocin on 6-OHDA-Induced Oxidative/Nitrosative Damage and Motor Behaviour in Hemiparkinsonian Rats. Malays J Med Sci 2016; 23:35-43. [PMID: 28090177 DOI: 10.21315/mjms2016.23.6.4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Accepted: 08/07/2016] [Indexed: 10/20/2022] Open
Abstract
BACKGROUND Crocin is considered to prevent oxidative stress-related diseases, such as ischemia and Alzheimer's. The aim of the present investigation was to evaluate the effects of crocin on motor behaviour and 6-OHDA-induced oxidative/nitrosative damage to the striatum in an experimental model of Parkinson's disease. METHODS Left medial forebrain bundle was lesioned by microinjection of 6-OHDA (16μg in 0.2% ascorbate-saline). Crocin (30 and 60 mg/kg) was injected intraperitoneally three days before surgery until six weeks. Rotational behaviour and biochemical analysis were used to evaluate the effect of crocin in a unilateral 6-OHDA-induced model of Parkinson's disease. RESULTS The contralateral rotations induced by apomorphine in 6-OHDA lesioned group were highly significant (P < 0.001) as compared to the sham group. Moreover, chronic administration of crocin at doses of 30 and 60 mg/kg over six weeks did not change the rotations. The TBARS and nitrite levels in the striatum were also significantly (P < 0.05) increased in lesioned group. Treatment with crocin at a dose of 60 mg/kg significantly decreased the nitrite levels (P < 0.05) in the striatum. CONCLUSION Crocin at a dose of 60 mg/kg could be effective in preventing the nitrosative damage in the striatum. Further investigations using higher doses of crocin is suggested to get the full neuroprotective effects of crocin in Parkinson's disease.
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Affiliation(s)
- Maryam Hosseini
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Ziba Rajaei
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Neurocognitive Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hojjatallah Alaei
- Isfahan Neurosciences Research Center, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
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Yafarova GG, Andrianov VV, Yagudin RK, Shaikhutdinov II, Gainutdinov KL. Nitric Oxide Production in the Rat Spinal Cord, Heart, and Liver After Spinal Cord Injury. BIONANOSCIENCE 2016. [DOI: 10.1007/s12668-016-0229-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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46
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Fu S, Lv R, Wang L, Hou H, Liu H, Shao S. Resveratrol, an antioxidant, protects spinal cord injury in rats by suppressing MAPK pathway. Saudi J Biol Sci 2016; 25:259-266. [PMID: 29472775 PMCID: PMC5815991 DOI: 10.1016/j.sjbs.2016.10.019] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2016] [Revised: 10/22/2016] [Accepted: 10/26/2016] [Indexed: 01/25/2023] Open
Abstract
Resveratrol, a polyphenol found in various plants, including grapes, plums and peanuts has shown various medIRInal properties, including antioxidant, protection of cardiovascular disease and cancer risk. However, the effects of resveratrol on spinal cord reperfusion injury have not been investigated. Hence, the present study was designed to evaluate the effect of resveratrol on nitric oxide synthase (iNOS)/p38MAPK signaling pathway and to elucidate its regulating effect on the protection of spinal cord injury. Spinal cord ischemia–reperfusion injury (IRI) was performed by the infrarenal abdominal aorta with mini aneurysm clip model. The expressions of iNOS and p38MAPK and the levels of biochemical parameters, including nitrite/nitrate, malondialdehyde (MDA), advanced oxidation products (AOPP), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were measured in control and experimental groups. IRI-induced rats treated with 10 mg/kg resveratrol protected spinal cord from ischemia injury as supported by improved biological parameters measured in spinal cord tissue homogenates. The resveratrol treatment significantly decreased the levels of plasma nitrite/nitrate, iNOS mRNA and protein expressions and phosphorylation of p38MAPK in IRI-induced rats. Further, IRI-produced free radicals were reduced by resveratrol treatment by increasing enzymatic and non-enzymatic antioxidant levels such as GSH, SOD and CAT. Taken together, administration of resveratrol protects the damage caused by spinal cord ischemia with potential mechanism of suppressing the activation of iNOS/p38MAPK pathway and subsequent reduction of oxidative stress due to IRI.
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Affiliation(s)
- Song Fu
- Department of Spinal, The Wendeng Osteopathic Hospital, Weihai City, Shandong Province 264400, China
| | - Renhua Lv
- Department of Orthopaedics, Wendeng Central Hospital, Weihai City, Shandong Province 264400, China
| | - Longqiang Wang
- Department of Spinal, The Wendeng Osteopathic Hospital, Weihai City, Shandong Province 264400, China
| | - Haitao Hou
- Department of Spinal, The Wendeng Osteopathic Hospital, Weihai City, Shandong Province 264400, China
| | - Haijun Liu
- Department of Spinal, The Wendeng Osteopathic Hospital, Weihai City, Shandong Province 264400, China
| | - Shize Shao
- Department of Spinal, The Wendeng Osteopathic Hospital, Weihai City, Shandong Province 264400, China
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Casili G, Impellizzeri D, Cordaro M, Esposito E, Cuzzocrea S. B-Cell Depletion with CD20 Antibodies as New Approach in the Treatment of Inflammatory and Immunological Events Associated with Spinal Cord Injury. Neurotherapeutics 2016; 13:880-894. [PMID: 27215219 PMCID: PMC5081113 DOI: 10.1007/s13311-016-0446-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Spinal cord injury (SCI) is a highly debilitating pathology that has irreversible impacts and results in functional loss. We evaluated the anti-inflammatory and immunologic role of antibody-mediated depletion of B cells through the glycoengineered anti-muCD20 antibody (18B12) in an experimental model of spinal cord compression, in vivo and ex vivo. Intraperitoneal 18B12 was administered at a dose of 30 mg/kg, 1 h and 6 h after SCI, and mice were sacrificed 24 h after trauma. We demonstrated, in vivo, that 18B12 slowed severe hindlimb motor dysfunction (Basso Mouse Scale score) and neuronal death by histological evaluation in SCI mice, as well as decreased expression of nuclear factor-kB, inducible nitric oxide synthase, cytokines, and glial fibrillary acidic protein. Also, 18B12 reduced expression of microglia, just as it lowered the expression of B and T lymphocytes. Moreover, in spinal cord organotypic cultures, pretreatment with 18B12 significantly reduced nitric oxide expression and protected cells from cell death [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay]. In this study, we showed that 18B12 treatment reduces the development of inflammation and tissue injury by alteration of the immune system associated with SCI. This study increases the current knowledge that B-cell depletion is able to exert immunomodulating actions in damaged spinal cords.
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Affiliation(s)
- Giovanna Casili
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres n°31 98166, Messina, Italy
| | - Daniela Impellizzeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres n°31 98166, Messina, Italy
| | - Marika Cordaro
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres n°31 98166, Messina, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres n°31 98166, Messina, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres n°31 98166, Messina, Italy.
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
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48
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Visavadiya NP, Patel SP, VanRooyen JL, Sullivan PG, Rabchevsky AG. Cellular and subcellular oxidative stress parameters following severe spinal cord injury. Redox Biol 2016; 8:59-67. [PMID: 26760911 PMCID: PMC4712315 DOI: 10.1016/j.redox.2015.12.011] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/24/2015] [Accepted: 12/29/2015] [Indexed: 01/11/2023] Open
Abstract
The present study undertook a comprehensive assessment of the acute biochemical oxidative stress parameters in both cellular and, notably, mitochondrial isolates following severe upper lumbar contusion spinal cord injury (SCI) in adult female Sprague Dawley rats. At 24h post-injury, spinal cord tissue homogenate and mitochondrial fractions were isolated concurrently and assessed for glutathione (GSH) content and production of nitric oxide (NO(•)), in addition to the presence of oxidative stress markers 3-nitrotyrosine (3-NT), protein carbonyl (PC), 4-hydroxynonenal (4-HNE) and lipid peroxidation (LPO). Moreover, we assessed production of superoxide (O2(•-)) and hydrogen peroxide (H2O2) in mitochondrial fractions. Quantitative biochemical analyses showed that compared to sham, SCI significantly lowered GSH content accompanied by increased NO(•) production in both cellular and mitochondrial fractions. SCI also resulted in increased O2(•-) and H2O2 levels in mitochondrial fractions. Western blot analysis further showed that reactive oxygen/nitrogen species (ROS/RNS) mediated PC and 3-NT production were significantly higher in both fractions after SCI. Conversely, neither 4-HNE levels nor LPO formation were increased at 24h after injury in either tissue homogenate or mitochondrial fractions. These results indicate that by 24h post-injury ROS-induced protein oxidation is more prominent compared to lipid oxidation, indicating a critical temporal distinction in secondary pathophysiology that is critical in designing therapeutic approaches to mitigate consequences of oxidative stress.
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Affiliation(s)
- Nishant P Visavadiya
- Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY 40536-0509, USA
| | - Samir P Patel
- Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY 40536-0509, USA.
| | - Jenna L VanRooyen
- Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY 40536-0509, USA
| | - Patrick G Sullivan
- Spinal Cord and Brain Injury Research Center, Department of Anatomy & Neurobiology, University of Kentucky, Lexington, KY 40536-0509, USA
| | - Alexander G Rabchevsky
- Spinal Cord and Brain Injury Research Center, Department of Physiology, University of Kentucky, Lexington, KY 40536-0509, USA
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49
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Anwar MA, Al Shehabi TS, Eid AH. Inflammogenesis of Secondary Spinal Cord Injury. Front Cell Neurosci 2016; 10:98. [PMID: 27147970 PMCID: PMC4829593 DOI: 10.3389/fncel.2016.00098] [Citation(s) in RCA: 314] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Accepted: 03/30/2016] [Indexed: 12/30/2022] Open
Abstract
Spinal cord injury (SCI) and spinal infarction lead to neurological complications and eventually to paraplegia or quadriplegia. These extremely debilitating conditions are major contributors to morbidity. Our understanding of SCI has certainly increased during the last decade, but remains far from clear. SCI consists of two defined phases: the initial impact causes primary injury, which is followed by a prolonged secondary injury consisting of evolving sub-phases that may last for years. The underlying pathophysiological mechanisms driving this condition are complex. Derangement of the vasculature is a notable feature of the pathology of SCI. In particular, an important component of SCI is the ischemia-reperfusion injury (IRI) that leads to endothelial dysfunction and changes in vascular permeability. Indeed, together with endothelial cell damage and failure in homeostasis, ischemia reperfusion injury triggers full-blown inflammatory cascades arising from activation of residential innate immune cells (microglia and astrocytes) and infiltrating leukocytes (neutrophils and macrophages). These inflammatory cells release neurotoxins (proinflammatory cytokines and chemokines, free radicals, excitotoxic amino acids, nitric oxide (NO)), all of which partake in axonal and neuronal deficit. Therefore, our review considers the recent advances in SCI mechanisms, whereby it becomes clear that SCI is a heterogeneous condition. Hence, this leads towards evidence of a restorative approach based on monotherapy with multiple targets or combinatorial treatment. Moreover, from evaluation of the existing literature, it appears that there is an urgent requirement for multi-centered, randomized trials for a large patient population. These clinical studies would offer an opportunity in stratifying SCI patients at high risk and selecting appropriate, optimal therapeutic regimens for personalized medicine.
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Affiliation(s)
- M Akhtar Anwar
- Department of Biological and Environmental Sciences, Qatar University Doha, Qatar
| | | | - Ali H Eid
- Department of Biological and Environmental Sciences, Qatar UniversityDoha, Qatar; Department of Pharmacology and Toxicology, Faculty of Medicine, American University of BeirutBeirut, Lebanon
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50
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Bedreag OH, Papurica M, Rogobete AF, Sarandan M, Cradigati CA, Vernic C, Dumbuleu CM, Nartita R, Sandesc D. New perspectives of volemic resuscitation in polytrauma patients: a review. BURNS & TRAUMA 2016; 4:5. [PMID: 27574675 PMCID: PMC4964009 DOI: 10.1186/s41038-016-0029-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 01/21/2016] [Indexed: 01/13/2023]
Abstract
Nowadays, fluid resuscitation of multiple trauma patients is still a challenging therapy. Existing therapies for volume replacement in severe haemorrhagic shock can lead to adverse reactions that may be fatal for the patient. Patients presenting with multiple trauma often develop hemorrhagic shock, which triggers a series of metabolic, physiological and cellular dysfunction. These disorders combined, lead to complications that significantly decrease survival rate in this subset of patients. Volume and electrolyte resuscitation is challenging due to many factors that overlap. Poor management can lead to post-resuscitation systemic inflammation causing multiple organ failure and ultimately death. In literature, there is no exact formula for this purpose, and opinions are divided. This paper presents a review of modern techniques and current studies regarding the management of fluid resuscitation in trauma patients with hemorrhagic shock. According to the literature and from clinical experience, all aspects regarding post-resuscitation period need to be considered. Also, for every case in particular, emergency therapy management needs to be rigorously respected considering all physiological, biochemical and biological parameters.
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Affiliation(s)
- Ovidiu Horea Bedreag
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital "Pius Brinzeu", Bd. Iosif Bulbuca nr.10, Timisoara, Timis Romania ; Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Marius Papurica
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital "Pius Brinzeu", Bd. Iosif Bulbuca nr.10, Timisoara, Timis Romania ; Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Alexandru Florin Rogobete
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital "Pius Brinzeu", Bd. Iosif Bulbuca nr.10, Timisoara, Timis Romania ; Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania ; Faculty of Chemistry, Biology, Geography, West University of Timisoara, Timisoara, Romania
| | - Mirela Sarandan
- Clinic of Anaesthesia and Intensive Care "Casa Austria", Emergency County Hospital "Pius Brinzeu", Timisoara, Romania
| | - Carmen Alina Cradigati
- Clinic of Anaesthesia and Intensive Care "Casa Austria", Emergency County Hospital "Pius Brinzeu", Timisoara, Romania
| | - Corina Vernic
- Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
| | - Corina Maria Dumbuleu
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital "Pius Brinzeu", Bd. Iosif Bulbuca nr.10, Timisoara, Timis Romania
| | - Radu Nartita
- Faculty of Chemistry, Biology, Geography, West University of Timisoara, Timisoara, Romania
| | - Dorel Sandesc
- Clinic of Anaesthesia and Intensive Care, Emergency County Hospital "Pius Brinzeu", Bd. Iosif Bulbuca nr.10, Timisoara, Timis Romania ; Faculty of Medicine, "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania
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