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Abbaszadeh F, Jorjani M, Joghataei MT, Raminfard S, Mehrabi S. Astaxanthin ameliorates spinal cord edema and astrocyte activation via suppression of HMGB1/TLR4/NF-κB signaling pathway in a rat model of spinal cord injury. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:3075-3086. [PMID: 37145127 DOI: 10.1007/s00210-023-02512-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 04/25/2023] [Indexed: 05/06/2023]
Abstract
Spinal cord edema is a quick-onset phenomenon with long-term effects. This complication is associated with inflammatory responses, as well as poor motor function. No effective treatment has been developed against spinal edema, which urges the need to provide novel therapies. Astaxanthin (AST) is a fat-soluble carotenoid with anti-inflammatory effects and a promising candidate for treating neurological disorders. This study aimed to investigate the underlying mechanism of AST on the inhibition of spinal cord edema, astrocyte activation, and reduction of inflammatory responsesin a rat compression spinal cord injury (SCI) model. Male rats underwent laminectomy at thoracic 8-9, and the SCI model was induced using an aneurysm clip. After SCI, rats received dimethyl sulfoxide or AST via intrathecal injection. The effects of AST were examined on the motor function, spinal cord edema, integrity of blood-spinal cord barrier (BSCB), and expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), glial fibrillary acidic protein (GFAP), and aquaporin-4 (AQP4), and matrix metallopeptidase- 9 (MMP-9) post-SCI. We showed that AST potentially improved the recovery of motor function and inhibited the spinal cord edema via maintaining the integrity of BSCB, reducing the expression of HMGB1, TLR4, and NF-κB, MMP-9 as well as downregulation of astrocyte activation (GFAP) and AQP4 expression. AST improves motor function and reduces edema and inflammatory responses in the spinal tissue. These effects are mediated by suppression of the HMGB1/TLR4/NF-κB signaling pathway, suppressing post-SCI astrocyte activation, and decreasing AQP4 and MMP-9 expression.
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Affiliation(s)
- Fatemeh Abbaszadeh
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Science, Tehran, Iran
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoumeh Jorjani
- Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mohammad Taghi Joghataei
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Science, Tehran, Iran.
- Department of Innovation in Medical Education, Faculty of Medicine, Ottawa University, Ottawa, Canada.
| | - Samira Raminfard
- Neuroimaging and Analysis Group, Research Center for Molecular and Cellular Imaging, Advanced Medical Technologies and Equipment Institue, Tehran University of Medical Sciences, Tehran, Iran
| | - Soraya Mehrabi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Science, Tehran, Iran
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Ozkizilcik A, Sharma A, Feng L, Muresanu DF, Tian ZR, Lafuente JV, Buzoianu AD, Nozari A, Wiklund L, Sharma HS. Nanowired delivery of antibodies to tau and neuronal nitric oxide synthase together with cerebrolysin attenuates traumatic brain injury induced exacerbation of brain pathology in Parkinson's disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2023; 171:83-121. [PMID: 37783564 DOI: 10.1016/bs.irn.2023.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2023]
Abstract
Concussive head injury (CHI) is one of the major risk factors for developing Parkinson's disease in later life of military personnel affecting lifetime functional and cognitive disturbances. Till date no suitable therapies are available to attenuate CHI or PD induced brain pathology. Thus, further exploration of novel therapeutic agents are highly warranted using nanomedicine in enhancing the quality of life of veterans or service members of US military. Since PD or CHI induces oxidative stress and perturbs neurotrophic factors regulation associated with phosphorylated tau (p-tau) deposition, a possibility exists that nanodelivery of agents that could enhance neurotrophic factors balance and attenuate oxidative stress could be neuroprotective in nature. In this review, nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors and active peptide fragments together with monoclonal antibodies to neuronal nitric oxide synthase (nNOS) with p-tau antibodies was examined in PD following CHI in model experiments. Our results suggest that combined administration of nanowired antibodies to nNOS and p-tau together with cerebrolysin significantly attenuated CHI induced exacerbation of PD brain pathology. This combined treatment also has beneficial effects in CHI or PD alone, not reported earlier.
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Affiliation(s)
- Asya Ozkizilcik
- Dept. Biomedical Engineering, University of Arkansas, Fayetteville, AR, United Staes
| | - Aruna Sharma
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Dept. of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
| | - Lianyuan Feng
- Department of Neurology, Bethune International Peace Hospital, Zhongshan Road (West), Shijiazhuang, Hebei Province, P.R. China
| | - Dafin F Muresanu
- Dept. Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; ''RoNeuro'' Institute for Neurological Research and Diagnostic, Mircea Eliade Street, Cluj-Napoca, Romania
| | - Z Ryan Tian
- Dept. Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - José Vicente Lafuente
- LaNCE, Dept. 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
| | - Ala Nozari
- Department of Anesthesiology, Boston University, Albany str, Boston MA, United States
| | - Lars Wiklund
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Dept. 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), Dept. of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden.
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3
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Sharma A, Muresanu DF, Patnaik R, Menon PK, Tian ZR, Sahib S, Castellani RJ, Nozari A, Lafuente JV, Buzoianu AD, Skaper SD, Bryukhovetskiy I, Manzhulo I, Wiklund L, Sharma HS. Histamine H3 and H4 receptors modulate Parkinson's disease induced brain pathology. Neuroprotective effects of nanowired BF-2649 and clobenpropit with anti-histamine-antibody therapy. PROGRESS IN BRAIN RESEARCH 2021; 266:1-73. [PMID: 34689857 DOI: 10.1016/bs.pbr.2021.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives. PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology. However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases. These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology. In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations. Our investigation shows that chronic administration of conventional or TiO2 nanowired BF 2649 (1mg/kg, i.p.) or CLBPT (1mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25μL) significantly thwarted ASNC and p-tau levels in the SNpC and STr and reduced PD induced brain pathology. These observations are the first to show the involvement of histamine receptors in PD and opens new avenues for the development of novel drug strategies in clinical strategies for PD, not reported earlier.
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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
| | - Ranjana Patnaik
- Department of Biomaterials, School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - Preeti K Menon
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Seaab Sahib
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - 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
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Stephen D Skaper
- Anesthesiology & Intensive Care, Department of Pharmacology, University of Padua, Padova, Italy
| | - Igor Bryukhovetskiy
- Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; Laboratory of Pharmacology, National Scientific Center of Marine Biology, Far East Branch of the Russian Academy of Sciences, 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
| | - 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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Sharma HS, Lafuente JV, Muresanu DF, Sahib S, Tian ZR, Menon PK, Castellani RJ, Nozari A, Buzoianu AD, Sjöquist PO, Patnaik R, Wiklund L, Sharma A. Neuroprotective effects of insulin like growth factor-1 on engineered metal nanoparticles Ag, Cu and Al induced blood-brain barrier breakdown, edema formation, oxidative stress, upregulation of neuronal nitric oxide synthase and brain pathology. PROGRESS IN BRAIN RESEARCH 2021; 266:97-121. [PMID: 34689867 DOI: 10.1016/bs.pbr.2021.06.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Military personnel are vulnerable to environmental or industrial exposure of engineered nanoparticles (NPs) from metals. Long-term exposure of NPs from various sources affect sensory-motor or cognitive brain functions. Thus, a possibility exists that chronic exposure of NPs affect blood-brain barrier (BBB) breakdown and brain pathology by inducing oxidative stress and/or nitric oxide production. This hypothesis was examined in the rat intoxicated with Ag, Cu or Al (50-60nm) nanoparticles (50mg/kg, i.p. once daily) for 7 days. In these NPs treated rats the BBB permeability, brain edema, neuronal nitric oxide synthase (nNOS) immunoreactivity and brain oxidants levels, e.g., myeloperoxidase (MP), malondialdehyde (MD) and glutathione (GT) was examined on the 8th day. Cu and Ag but not Al nanoparticles increased the MP and MD levels by twofold in the brain although, GT showed 50% decline. At this time increase in brain water content and BBB breakdown to protein tracers were seen in areas exhibiting nNOS positive neurons and cell injuries. Pretreatment with insulin like growth factor-1 (IGF-1) in high doses (1μg/kg, i.v. but not 0.5μg/kg daily for 7 days) together with NPs significantly reduced the oxidative stress, nNOS upregulation, BBB breakdown, edema formation and cell injuries. These novel observations demonstrate that (i) NPs depending on their metal constituent (Cu, Ag but not Al) induce oxidative stress and nNOS expression leading to BBB disruption, brain edema and cell damage, and (ii) IGF-1 depending on doses exerts powerful neuroprotection against nanoneurotoxicity, 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.
| | - José Vicente Lafuente
- LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain
| | - Dafin F Muresanu
- Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania; "RoNeuro" Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania
| | - 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
| | - Preeti K Menon
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - 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
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Per-Ove Sjöquist
- Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - 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
| | - 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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Chen X, Xiang X, Xie T, Chen Z, Mou Y, Gao Z, Xie X, Song M, Huang H, Gao Z, Chen M. Memantine protects blood-brain barrier integrity and attenuates neurological deficits through inhibiting nitric oxide synthase ser1412 phosphorylation in intracerebral hemorrhage rats: involvement of peroxynitrite-related matrix metalloproteinase-9/NLRP3 inflammasome activation. Neuroreport 2021; 32:228-237. [PMID: 33470757 PMCID: PMC7870044 DOI: 10.1097/wnr.0000000000001577] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 10/05/2020] [Indexed: 01/08/2023]
Abstract
Memantine has demonstrated beneficial effects on several types of brain insults via therapeutic mechanisms mainly related to its activity as a receptor antagonist of N-methyl-d-aspartate. However, the influences of memantine on intracerebral hemorrhage (ICH) remain obscure. This research probed into the neurovascular protective mechanisms of memantine after ICH and its impacts on neuronal nitric oxide synthase (nNOS) ser1412 phosphorylation. ICH model was established by employing intrastriatal collagenase injection in rats. After modeling, rats were then allocated randomly into sham-operated (sham), vehicle-treated (ICH+V), and memantine-administrated (ICH+M) groups. Memantine (20 mg/kg/day) was intraperitoneally administered 30 min after ICH and thenceforth once daily. Rats were dedicated at 0.25, 6, 12, 24 h, 3 and 7 d post-ICH for measurement of corresponding indexes. Behavioral changes, brain edema, levels of nNOS ser1412 phosphorylation, peroxynitrite, matrix metalloproteinase (MMP)-9, NLRP3, IL-1β and numbers of dying neurons, as well as the cellular localization of gelatinolytic activity, were detected among the groups. Memantine improved the neurologic deficits and mitigated brain water content, levels of MMP-9, NLRP3, IL-1β and dying neurons. Additionally, treatment with memantine also reduced nNOS ser1412 phosphorylation and peroxynitrite formation compared with the ICH+V group at 24 h after ICH. In situ zymography simultaneously revealed that gelatinase activity was primarily colocalized with vessel walls and neurons. We concluded that memantine ameliorated blood-brain barrier disruption and neurologic dysfunction in an ICH rat model. The underlying mechanism might involve repression of nNOS ser1412 phosphorylation, as well as peroxynitrite-related MMP-9 and NLRP3 inflammasome activation.
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Affiliation(s)
- Xiaowei Chen
- Department of Neurosurgery, the First People’s Hospital of Jingmen City
| | - Xu Xiang
- Department of Neurosurgery, Jingmen Clinical Medical School, Hubei Minzu University, Hubei Province
| | - Teng Xie
- Department of Neurosurgery, the First People’s Hospital of Jingmen City
| | - Zhijun Chen
- Department of Neurosurgery, the First People’s Hospital of Jingmen City
| | - Yu Mou
- Department of Neurosurgery, Jingmen Clinical Medical School, Hubei Minzu University, Hubei Province
| | - Zixu Gao
- The Second Clinical Medical College of Nanchang University
| | - Xun Xie
- The Second Clinical Medical College of Nanchang University
| | - Min Song
- The Second Clinical Medical College of Nanchang University
| | - Hui Huang
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Ziyun Gao
- Department of Neurosurgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Min Chen
- The Second Clinical Medical College of Nanchang University
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Kwiecien JM, Dąbrowski W, Yaron JR, Zhang L, Delaney KH, Lucas AR. The Role of Astrogliosis in Formation of the Syrinx in Spinal Cord Injury. Curr Neuropharmacol 2021; 19:294-303. [PMID: 32691715 PMCID: PMC8033977 DOI: 10.2174/1570159x18666200720225222] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/09/2020] [Accepted: 07/16/2020] [Indexed: 12/28/2022] Open
Abstract
A massive localized trauma to the spinal cord results in complex pathologic events driven by necrosis and vascular damage which in turn leads to hemorrhage and edema. Severe, destructive and very protracted inflammatory response is characterized by infiltration by phagocytic macrophages of a site of injury which is converted into a cavity of injury (COI) surrounded by astroglial reaction mounted by the spinal cord. The tissue response to the spinal cord injury (SCI) has been poorly understood but the final outcome appears to be a mature syrinx filled with the cerebrospinal fluid with related neural tissue loss and permanent neurologic deficits. This paper reviews known pathologic mechanisms involved in the formation of the COI after SCI and discusses the integrative role of reactive astrogliosis in mechanisms involved in the removal of edema after the injury. A large proportion of edema fluid originating from the trauma and then from vasogenic edema related to persistent severe inflammation, may be moved into the COI in an active process involving astrogliosis and specifically over-expressed aquaporins.
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Affiliation(s)
- Jacek M. Kwiecien
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Wojciech Dąbrowski
- Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, ul. Jaczewskiego 8, Lublin 20-090 Poland
| | - Jordan R Yaron
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ, U.S.A
| | - Liqiang Zhang
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ, U.S.A
| | - Kathleen H. Delaney
- Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada
| | - Alexandra R. Lucas
- Center for Personalized Diagnostics and Center for Immunotherapy, Vaccines and Virotherapy, Biodesign Institute, Arizona State University, Tempe, AZ, U.S.A
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Sahib S, Sharma A, Menon PK, Muresanu DF, Castellani RJ, Nozari A, Lafuente JV, Bryukhovetskiy I, Tian ZR, Patnaik R, Buzoianu AD, Wiklund L, Sharma HS. Cerebrolysin enhances spinal cord conduction and reduces blood-spinal cord barrier breakdown, edema formation, immediate early gene expression and cord pathology after injury. PROGRESS IN BRAIN RESEARCH 2020; 258:397-438. [PMID: 33223040 DOI: 10.1016/bs.pbr.2020.09.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Spinal cord evoked potentials (SCEP) are good indicators of spinal cord function in health and disease. Disturbances in SCEP amplitudes and latencies during spinal cord monitoring predict spinal cord pathology following trauma. Treatment with neuroprotective agents preserves SCEP and reduces cord pathology after injury. The possibility that cerebrolysin, a balanced composition of neurotrophic factors improves spinal cord conduction, attenuates blood-spinal cord barrier (BSCB) disruption, edema formation, and cord pathology was examined in spinal cord injury (SCI). SCEP is recorded from epidural space over rat spinal cord T9 and T12 segments after peripheral nerves stimulation. SCEP consists of a small positive peak (MPP), followed by a prominent negative peak (MNP) that is stable before SCI. A longitudinal incision (2mm deep and 5mm long) into the right dorsal horn (T10 and T11 segments) resulted in an immediate long-lasting depression of the rostral MNP with an increase in the latencies. Pretreatment with either cerebrolysin (CBL 5mL/kg, i.v. 30min before) alone or TiO2 nanowired delivery of cerebrolysin (NWCBL 2.5mL/kg, i.v.) prevented the loss of MNP amplitude and even enhanced further from the pre-injury level after SCI without affecting latencies. At 5h, SCI induced edema, BSCB breakdown, and cell injuries were significantly reduced by CBL and NWCBL pretreatment. Interestingly this effect on SCEP and cord pathology was still prominent when the NWCBL was delivered 2min after SCI. Moreover, expressions of c-fos and c-jun genes that are prominent at 5h in untreated SCI are also considerably reduced by CBL and NWCBL treatment. These results are the first to show that CBL and NWCBL enhanced SCEP activity and thwarted the development of cord pathology after SCI. Furthermore, NWCBL in low doses has superior neuroprotective effects on SCEP and cord pathology, not reported earlier. The functional significance and future clinical potential of CBL and NWCBL in SCI are discussed.
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Affiliation(s)
- Seaab Sahib
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - 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.
| | - Preeti K Menon
- International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden; Department of Biochemistry and Biophysics, Stockholm University, Stockholm, 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
| | - Igor Bryukhovetskiy
- Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia; Laboratory of Pharmacology, National Scientific Center of Marine Biology, Far East Branch of the Russian Academy of Sciences, Vladivostok, Russia
| | - Z Ryan Tian
- Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, United States
| | - Ranjana Patnaik
- Department of Biomaterials, School of Biomedical Engineering, Indian Institute of Technology, Banaras Hindu University, Varanasi, India
| | - Anca D Buzoianu
- Department of Clinical Pharmacology and Toxicology, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - 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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Zhang C, Hu A, Jing Y, Yang D, Li J. Mannitol Reduces Spinal Cord Edema in Rats with Acute Traumatic Spinal Cord Injury. LETT DRUG DES DISCOV 2020. [DOI: 10.2174/1570180816666190731112158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
The research about anti-edema effects of mannitol on acute traumatic spinal
cord injury (SCI) in rats is rare.
Objective:
This study aimed to explore the effect of mannitol on spinal cord edema after SCI in rats.
Methods:
Seventy-eight adult female rats were assigned to three groups randomly: a sham control
group (n = 18), a contusion and normal saline contrast group (n=30), and a contusion and mannitol
treatment group (n=30). We used the open-field test to estimate the functional recovery of rats weekly.
Spinal cord water content was measured to determine the spinal cord edema. The ultrastructure
features of the injured dorsolateral spinal cord were determined on the 7th day after SCI by HE staining.
Results:
The mannitol group had greatly improved Basso-Beattie-Bresnahan (BBB) scores when
compared with the saline contrast group. The spinal cord water content was increased significantly
after SCI, and there was no significant difference in the water content between the NaCl and mannitol
groups 1 day after SCI. The water content at 3 and 7 days after SCI was significantly lower in the
mannitol group than in the NaCl group (p < 0.05). Mannitol can reduce spinal cord edema by increasing
the number of red blood cells in the injured spinal cord and decrease the ratio (dorsoventral
diameter/ mediolateral diameter) of spinal cord 7 days post-SCI.
Conclusion:
Mannitol increases recovery of motor function in rats, reduces spinal cord edema and
increases the number of red blood cells in the injured spinal cord, decreasing the ratio of spinal cord
to reduce pressure.
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Affiliation(s)
- Chao Zhang
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China
| | - Anming Hu
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China
| | - Yingli Jing
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China
| | - Degang Yang
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China
| | - Jianjun Li
- School of Rehabilitation Medicine, Capital Medical University, Beijing 100068, China
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Luo H, Li P, Zhang H, Diao X, Kong B. Nitrosylmyoglobin formation in meat by Lactobacillus fermentum AS1.1880 is due to its nitric oxide synthase activity. Meat Sci 2020; 166:108122. [PMID: 32240903 DOI: 10.1016/j.meatsci.2020.108122] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 03/09/2020] [Accepted: 03/16/2020] [Indexed: 12/30/2022]
Abstract
The objective of this study was to clarify whether formation of nitrosylmyoglobin (MbFeIINO) by Lactobacillus fermentum AS1.1880 in meat is due to nitric oxide synthase (NOS) activity. Confocal laser scanning microscopy exhibited strong green fluorescence in the L. fermentum sample treated with a nitric oxide (NO)-specific probe, directly indicating that NO was produced. Furthermore, determination of NOS activity based on the presence of NO metabolites indicated the existence of NOS in L.fermentum. A NOS inhibitor, NG-nitro-L-arginine methyl ester, significantly inhibited the activity of NOS in L.fermentum (P < 0.05). Futhermore, NOS protein was detected in L.fermentum by Western blot analysis. L-arginine addition largely increased the NOS activity of L.fermentum (P < 0.05). In meat batters, the redness of a sample inoculated with L.fermentum was higher than that of the control and colour was significantly improved with the addition of L-arginine (P < 0.05), indicating that more MbFeIINO was formed.
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Affiliation(s)
- Huiting Luo
- College of Food Science, Northeast Agricultural University, Harbin, Heilongjiang, 150030, China
| | - Peijun Li
- School of Food and Biological Engineering, Hefei University of Technology, Hefei, Anhui, 230009, China
| | - Hongwei Zhang
- College of Food Science, Northeast Agricultural University, Harbin, Heilongjiang, 150030, China
| | - Xinping Diao
- College of Animal Science, Northeast Agricultural University, Harbin, Heilongjiang, 150030, China
| | - Baohua Kong
- College of Food Science, Northeast Agricultural University, Harbin, Heilongjiang, 150030, China.
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10
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Nanodelivery of cerebrolysin reduces pathophysiology of Parkinson's disease. PROGRESS IN BRAIN RESEARCH 2019; 245:201-246. [DOI: 10.1016/bs.pbr.2019.03.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Sharma A, Castellani RJ, Smith MA, Muresanu DF, Dey PK, Sharma HS. 5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2019; 146:1-44. [DOI: 10.1016/bs.irn.2019.06.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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12
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Khan M, Dhammu TS, Singh I, Singh AK. Amelioration of spinal cord injury in rats by blocking peroxynitrite/calpain activity. BMC Neurosci 2018; 19:50. [PMID: 30103682 PMCID: PMC6090709 DOI: 10.1186/s12868-018-0450-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 08/07/2018] [Indexed: 01/09/2023] Open
Abstract
Background Spinal cord injury (SCI) is one of the leading causes of disability and chronic pain. In SCI-induced pathology, homeostasis of the nitric oxide (NO) metabolome is lost. Major NO metabolites such as S-nitrosoglutathione (GSNO) and peroxynitrite are reported to play pivotal roles in regulating the activities of key cysteine proteases, calpains. While peroxynitrite (a metabolite of NO and superoxide) up regulates the activities of calpains leading to neurodegeneration, GSNO (a metabolite of NO and glutathione) down regulates the activities of calpains leading to neuroprotection. In this study, effect of GSNO on locomotor function and pain threshold and their relationship with the levels of peroxynitrite and the activity of calpain in the injured spinal cord were investigated using a 2-week rat model of contusion SCI.
Results SCI animals were initially treated with GSNO at 2 h after the injury followed by a once daily dose of GSNO for 14 days. Locomotor function was evaluated by “Basso Beattie and Bresnahan (BBB) locomotor rating scale” and pain by mechanical allodynia. Peroxynitrite level, as expression of 3-nitrotyrosine (3-NT), calpain activity, as the degradation products of calpain substrate alpha II spectrin, and nNOS activity, as the expression phospho nNOS, were measured by western blot analysis. Treatment with GSNO improved locomotor function and mitigated pain. The treatment also reduced the levels of peroxynitrite (3-NT) and decreased activity of calpains. Reduced levels of peroxynitrite resulted from the GSNO-mediated inhibition of aberrant activity of neuronal nitric oxide synthase (nNOS). Conclusions The data indicates that higher levels of 3-NT and aberrant activities of nNOS and calpains correlated with SCI pathology and functional deficits. Treatment with GSNO improved locomotor function and mitigated mechanical allodynia acutely post-injury. Because GSNO shows potential to ameliorate experimental SCI, we discuss implications for GSNO therapy in clinical SCI research.
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Affiliation(s)
- Mushfiquddin Khan
- Department of Pediatrics, 508 Children's Research Institute, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC, 29425, USA.
| | - Tajinder S Dhammu
- Department of Pediatrics, 508 Children's Research Institute, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC, 29425, USA
| | - Inderjit Singh
- Department of Pediatrics, 508 Children's Research Institute, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC, 29425, USA.,Ralph H Johnson VA Medical Center, Charleston, SC, USA
| | - Avtar K Singh
- Ralph H Johnson VA Medical Center, Charleston, SC, USA.,Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA
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Nash KM, Schiefer IT, Shah ZA. Development of a reactive oxygen species-sensitive nitric oxide synthase inhibitor for the treatment of ischemic stroke. Free Radic Biol Med 2018; 115:395-404. [PMID: 29275014 PMCID: PMC11970191 DOI: 10.1016/j.freeradbiomed.2017.12.027] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Revised: 11/28/2017] [Accepted: 12/20/2017] [Indexed: 01/25/2023]
Abstract
Ischemic stroke is caused by a blockage of cerebral blood flow resulting in neuronal and glial hypoxia leading to inflammatory and reactive oxygen species (ROS)-mediated cell death. Nitric oxide (NO) formed by NO synthase (NOS) is known to be protective in ischemic stroke, however NOS has been shown to 'uncouple' under oxidative conditions to instead produce ROS. Nitrones are antioxidant molecules that are shown to trap ROS to then decompose and release NO. In this study, the nitrone 5 was designed such that its decomposition product is a NOS inhibitor, 6, effectively leading to NOS inhibition specifically at the site of ROS production. The ability of 5 to spin-trap radicals and decompose to 6 was observed using EPR and LC-MS/MS. The pro-drug concept was tested in vitro by measuring cell viability and 6 formation in SH-SY5Y cells subjected to oxygen glucose deprivation (OGD). 5 was found to be more efficacious and more potent than PBN, and was able to increase phospho-Akt while reducing nitrotyrosine and cleaved caspase-3 levels. 6 treatment, but not 5, was found to decrease NO production in LPS-stimulated microglia. Doppler flowmetry on anesthetized mice showed increased cerebral blood flow upon intravenous administration of 1mg/kg of 5, but a return to baseline upon administration of 10mg/kg, likely due to its dual nature of antioxidant/NO-donor and NOS-inhibition. Mice treated with 5 after permanent ischemia exhibited a >30% reduction in infarct volume, and higher formation of 6 in ischemic tissue resulting in region specific effects limited to the infarct area.
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Affiliation(s)
- Kevin M Nash
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, USA
| | - Isaac T Schiefer
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, OH 43614, USA.
| | - Zahoor A Shah
- Department of Medicinal and Biological Chemistry, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, OH 43614, USA.
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Yan X, Liu J, Wang X, Li W, Chen J, Sun H. Pretreatment with AQP4 and NKCC1 Inhibitors Concurrently Attenuated Spinal Cord Edema and Tissue Damage after Spinal Cord Injury in Rats. Front Physiol 2018; 9:6. [PMID: 29403391 PMCID: PMC5780344 DOI: 10.3389/fphys.2018.00006] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 01/04/2018] [Indexed: 12/19/2022] Open
Abstract
Spinal cord injury (SCI) affects more than 2.5 million people worldwide. Spinal cord edema plays critical roles in the pathological progression of SCI. This study aimed to delineate the roles of aquaporin 4 (AQP4) and Na+-K+-Cl− cotransporter 1 (NKCC1) in acute phase edema and tissue destruction after SCI and to explore whether inhibiting both AQP4 and NKCC1 could improve SCI-induced spinal edema and damage. Rat SCI model was established by modified Allen's method. Spinal cord water content, cerebrospinal fluid lactose dehydrogenase (LDH) activity, AQP4 and NKCC1 expression, and spinal cord pathology from 30 min to 7 days after SCI were monitored. Additionally, aforementioned parameters in rats treated with AQP4 and/or NKCC1 inhibitors were assessed 2 days after SCI. Spinal cord water content was significantly increased 1 h after SCI while AQP4 and NKCC1 expression and spinal fluid LDH activity elevated 6 h after SCI. Spinal cord edema and spinal cord destruction peaked around 24 h after SCI and maintained at high levels thereafter. Treating rats with AQP4 inhibitor TGN-020 and NKCC1 antagonist bumetanide significantly reduced spinal cord edema, tissue destruction, and AQP4 and NKCC1 expression after SCI in an additive manner. These results demonstrated the benefits of simultaneously inhibiting both AQP4 and NKCC1 after SCI.
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Affiliation(s)
- Xiaodong Yan
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Juanfang Liu
- Department of Clinical Aerospace Medicine, Fourth Military Medical University, Xi'an, China
| | - Xiji Wang
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Wenhao Li
- Cadet Brigade, Fourth Military Medical University, Xi'an, China
| | - Jingyuan Chen
- Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, Xi'an, China
| | - Honghui Sun
- Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
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Rosich K, Hanna BF, Ibrahim RK, Hellenbrand DJ, Hanna A. The Effects of Glial Cell Line-Derived Neurotrophic Factor after Spinal Cord Injury. J Neurotrauma 2017; 34:3311-3325. [DOI: 10.1089/neu.2017.5175] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Affiliation(s)
- Konstantin Rosich
- Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin
| | - Bishoy F. Hanna
- Department of Neurological Surgery, Ross University School of Medicine, Dominica, West Indies
| | - Rami K. Ibrahim
- Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin
| | - Daniel J. Hellenbrand
- Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin
- Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin
| | - Amgad Hanna
- Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin
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Timed Release of Cerebrolysin Using Drug-Loaded Titanate Nanospheres Reduces Brain Pathology and Improves Behavioral Functions in Parkinson’s Disease. Mol Neurobiol 2017; 55:359-369. [DOI: 10.1007/s12035-017-0747-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Methylprednisolone Administration Following Spinal Cord Injury Reduces Aquaporin 4 Expression and Exacerbates Edema. Mediators Inflamm 2017; 2017:4792932. [PMID: 28572712 PMCID: PMC5442433 DOI: 10.1155/2017/4792932] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 03/19/2017] [Indexed: 12/21/2022] Open
Abstract
Spinal cord injury (SCI) is an incapacitating condition that affects motor, sensory, and autonomic functions. Since 1990, the only treatment administered in the acute phase of SCI has been methylprednisolone (MP), a synthetic corticosteroid that has anti-inflammatory effects; however, its efficacy remains controversial. Although MP has been thought to help in the resolution of edema, there are no scientific grounds to support this assertion. Aquaporin 4 (AQP4), the most abundant component of water channels in the CNS, participates in the formation and elimination of edema, but it is not clear whether the modulation of AQP4 expression by MP plays any role in the physiopathology of SCI. We studied the functional expression of AQP4 modulated by MP following SCI in an experimental model in rats along with the associated changes in the permeability of the blood-spinal cord barrier. We analyzed these effects in male and female rats and found that SCI increased AQP4 expression in the spinal cord white matter and that MP diminished such increase to baseline levels. Moreover, MP increased the extravasation of plasma components after SCI and enhanced tissue swelling and edema. Our results lend scientific support to the increasing motion to avoid MP treatment after SCI.
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Pei JP, Fan LH, Nan K, Li J, Dang XQ, Wang KZ. HSYA alleviates secondary neuronal death through attenuating oxidative stress, inflammatory response, and neural apoptosis in SD rat spinal cord compression injury. J Neuroinflammation 2017; 14:97. [PMID: 28468657 PMCID: PMC5415746 DOI: 10.1186/s12974-017-0870-1] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 04/21/2017] [Indexed: 01/08/2023] Open
Abstract
Background Hydroxysafflor yellow A (HSYA) is a major active component of yellow pigment extracted from safflowers; this compound possesses potent neuroprotective effects both in vitro and in vivo. However, underlying mechanism of HSYA is not fully elucidated. The present study investigated the protective effects of HSYA in rat spinal cord compression injury model and related mechanisms involved. Methods Sprague–Dawley rats were divided as Sham, Control, and HSYA groups (n = 30 per group). Spinal cord injury (SCI) model was induced by application of vascular clips (force of 50 g, 1 min) to the dura at T9–T10 level of vertebra. Injured animals were administered with either HSYA (8 mg/kg at 1 and 6 h after injury, then 14 mg/kg, for a total of 7 days at 24-h time intervals) or equal volume of saline by intraperitoneal injection. Results From this experiment, we discovered that SCI in rats resulted in severe trauma, which is characterized by tissue damage, lipid peroxidation, neutrophil infiltration, inflammation mediator release, and neuronal apoptosis. However, HSYA treatment significantly reduced the following: (1) degree of tissue injury (histological score) and edema; (2) neutrophil infiltration (myeloperoxidase activity); (3) oxidative stress (superoxide dismutase, malondialdehyde, and nitric oxide); (4) pro-inflammatory cytokine expression (tumor necrosis factor-α, interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2); (5) nuclear factor-κB activation; (6) apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling staining and cysteine-aspartic protease-3 activity). Moreover, in a separate set of experiments, we clearly demonstrated that HSYA treatment significantly ameliorated recovery of limb function (as evaluated by Basso, Beattie, and Bresnahan behavioral recovery scores). Conclusions Treatment with HSYA restrains development of oxidative stress, inflammation response, and apoptotic events associated with SCI of rats, demonstrating that HSYA is a potential neuroprotectant for human SCI therapy.
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Affiliation(s)
- Jun-Peng Pei
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xi'an, 710004, Shaanxi Province, People's Republic of China
| | - Li-Hong Fan
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xi'an, 710004, Shaanxi Province, People's Republic of China.
| | - Kai Nan
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xi'an, 710004, Shaanxi Province, People's Republic of China
| | - Jia Li
- Department of Orthopaedics, the First Affiliated Hospital of Xi'an Jiaotong University, School of Medicine, Xi'an, 710061, China
| | - Xiao-Qian Dang
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xi'an, 710004, Shaanxi Province, People's Republic of China
| | - Kun-Zheng Wang
- Department of Orthopaedics, the Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 Xiwu Road, Xi'an, 710004, Shaanxi Province, People's Republic of China
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Ma S, Wang J, Liu L, Xia L, Tao R. Identification of temporal genes involved in the mechanisms of spinal cord injury. Spinal Cord 2017; 55:355-361. [PMID: 28071686 DOI: 10.1038/sc.2016.183] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Revised: 10/24/2016] [Accepted: 11/17/2016] [Indexed: 11/09/2022]
Abstract
OBJECTIVES As a high-cost neurological disability, spinal cord injury (SCI) can result in permanent paralysis and loss of sensation. To identify the temporal genes involved in the pathogenesis of SCI, we analysed the expression profile of GSE45006. METHODS GSE45006 was downloaded from Gene Expression Omnibus, including 20 SCI samples (samples at 1 day, 3 days, 1 week, 2 weeks and 8 weeks after injury, four repetitions for each time point) and 4 normal samples. The Bayesian Estimation of Temporal Regulation (BETR) and randomForest packages were used to screen the temporal genes and the top 100 temporal genes, respectively. Then, the gplots package and Pearson correlation analysis separately were used to perform hot map analysis and expression pattern clustering for the top 100 temporal genes. Using the clusterProfiler package and TargetMine tool, their potential functions were analysed by enrichment analyses. Moreover, interaction relationships between these temporal genes and pathways were investigated by pathway-gene crosslinking networks. RESULTS In total, 1907 temporal genes were identified. The top 100 temporal genes were obtained and divided into six clusters. Most of the gene functions were enriched in biological process categories. ARG1 and NOS3 in cluster 4 were enriched in biological process of arginine catabolic process. TGFβ2, TGFβ3, ALDH2 and ALDH3A2 were correlated with numerous pathways in the pathway-gene crosslinking network. Pathways related to TGFβ2 and TGFβ3 were connected to pathways related to ARG1 and NOS3 via ARG1. CONCLUSION Several temporal genes, including TGFβ2, TGFβ3, ALDH2, ALDH3A2, ARG1 and NOS3, might be involved in SCI.
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Affiliation(s)
- S Ma
- Department of Pain Management, Henan Provincial People's Hospital, The People's Hospital of Zhengzhou University, Zhengzhou, China
| | - J Wang
- Department of Pain Management, Henan Provincial People's Hospital, The People's Hospital of Zhengzhou University, Zhengzhou, China
| | - L Liu
- Department of Pain Management, Henan Provincial People's Hospital, The People's Hospital of Zhengzhou University, Zhengzhou, China
| | - L Xia
- Department of Pain Management, Henan Provincial People's Hospital, The People's Hospital of Zhengzhou University, Zhengzhou, China
| | - R Tao
- Department of Pain Management, Henan Provincial People's Hospital, The People's Hospital of Zhengzhou University, Zhengzhou, China
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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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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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Kumar H, Ropper AE, Lee SH, Han I. Propitious Therapeutic Modulators to Prevent Blood-Spinal Cord Barrier Disruption in Spinal Cord Injury. Mol Neurobiol 2016; 54:3578-3590. [PMID: 27194298 DOI: 10.1007/s12035-016-9910-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Accepted: 05/03/2016] [Indexed: 01/09/2023]
Abstract
The blood-spinal cord barrier (BSCB) is a specialized protective barrier that regulates the movement of molecules between blood vessels and the spinal cord parenchyma. Analogous to the blood-brain barrier (BBB), the BSCB plays a crucial role in maintaining the homeostasis and internal environmental stability of the central nervous system (CNS). After spinal cord injury (SCI), BSCB disruption leads to inflammatory cell invasion such as neutrophils and macrophages, contributing to permanent neurological disability. In this review, we focus on the major proteins mediating the BSCB disruption or BSCB repair after SCI. This review is composed of three parts. Section 1. SCI and the BSCB of the review describes critical events involved in the pathophysiology of SCI and their correlation with BSCB integrity/disruption. Section 2. Major proteins involved in BSCB disruption in SCI focuses on the actions of matrix metalloproteinases (MMPs), tumor necrosis factor alpha (TNF-α), heme oxygenase-1 (HO-1), angiopoietins (Angs), bradykinin, nitric oxide (NO), and endothelins (ETs) in BSCB disruption and repair. Section 3. Therapeutic approaches discusses the major therapeutic compounds utilized to date for the prevention of BSCB disruption in animal model of SCI through modulation of several proteins.
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Affiliation(s)
- Hemant Kumar
- Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea
| | - Alexander E Ropper
- Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA
| | - Soo-Hong Lee
- Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
| | - Inbo Han
- Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea.
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Yonan JM, Binder DK. Aquaporin-4 and spinal cord injury. World J Neurol 2016; 6:1-13. [DOI: 10.5316/wjn.v6.i1.1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 12/25/2015] [Accepted: 01/19/2016] [Indexed: 02/06/2023] Open
Abstract
Edema formation is a major problem following traumatic spinal cord injury (SCI) that acts to exacerbate secondary damage. Severity of edema correlates with reduced neurological outcome in human patients. To date, there are no effective treatments to directly resolve edema within the spinal cord. The aquaporin-4 (AQP4) water channel is found on membranes of astrocytic endfeet in direct contact with blood vessels, the glia limitans in contact with the cerebrospinal fluid and ependyma around the central canal. Being so locally expressed at the interface between fluid and tissue allow AQP4 channels to play an important role in the bidirectional regulation of water homeostasis under normal conditions and following trauma. With the need to better understand the pathophysiology underlying the devastating cellular events in SCI, animal models have become an integral part of exploration. Inevitably, several injury models have been developed (contusion, compression, transection) resulting in difficult interpretation between studies with conflicting results. This is true in the case of understanding the role of AQP4 in the progression and resolution of edema following SCI, whose role is still not completely understood and is highly dependent on the type of edema present (vasogenic vs cytotoxic). Here, we discuss regulation of AQP4 in varying injury models and the effects of potential therapeutic interventions on expression, edema formation and functional recovery. Better understanding of the precise role of AQP4 following a wide range of injuries will help to understand optimal treatment timing following human SCI for prime therapeutic benefit and enhanced neurological outcome.
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Schomberg D, Miranpuri G, Duellman T, Crowell A, Vemuganti R, Resnick D. Spinal cord injury induced neuropathic pain: Molecular targets and therapeutic approaches. Metab Brain Dis 2015; 30:645-58. [PMID: 25588751 DOI: 10.1007/s11011-014-9642-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 12/05/2014] [Indexed: 10/24/2022]
Abstract
Neuropathic pain, especially that resulting from spinal cord injury, is a tremendous clinical challenge. A myriad of biological changes have been implicated in producing these pain states including cellular interactions, extracellular proteins, ion channel expression, and epigenetic influences. Physiological consequences of these changes are varied and include functional deficits and pain responses. Developing therapies that effectively address the cause of these symptoms require a deeper knowledge of alterations in the molecular pathways. Matrix metalloproteinases and tissue inhibitors of metalloproteinases are two promising therapeutic targets. Matrix metalloproteinases interact with and influence many of the studied pain pathways. Gene expression of ion channels and inflammatory mediators clearly contributes to neuropathic pain. Localized and time dependent targeting of these proteins could alleviate and even prevent neuropathic pain from developing. Current therapeutic options for neuropathic pain are limited primarily to analgesics targeting the opioid pathway. Therapies directed at molecular targets are highly desirable and in early stages of development. These include transplantation of exogenously engineered cell populations and targeted gene manipulation. This review describes specific molecular targets amenable to therapeutic intervention using currently available delivery systems.
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Affiliation(s)
- Dominic Schomberg
- Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, Madison, WI, 53792, USA
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Moghimi E, Solomon JA, Gianforcaro A, Hamadeh MJ. Dietary Vitamin D3 Restriction Exacerbates Disease Pathophysiology in the Spinal Cord of the G93A Mouse Model of Amyotrophic Lateral Sclerosis. PLoS One 2015; 10:e0126355. [PMID: 26020962 PMCID: PMC4447353 DOI: 10.1371/journal.pone.0126355] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 03/22/2015] [Indexed: 12/11/2022] Open
Abstract
Background Dietary vitamin D3 (D3) restriction reduces paw grip endurance and motor performance in G93A mice, and increases inflammation and apoptosis in the quadríceps of females. ALS, a neuromuscular disease, causes progressive degeneration of motor neurons in the brain and spinal cord. Objective We analyzed the spinal cords of G93A mice following dietary D3 restriction at 2.5% the adequate intake (AI) for oxidative damage (4-HNE, 3-NY), antioxidant enzymes (SOD2, catalase, GPx1), inflammation (TNF-α, IL-6, IL-10), apoptosis (bax/bcl-2 ratio, cleaved/pro-caspase 3 ratio), neurotrophic factor (GDNF) and neuron count (ChAT, SMI-36/SMI-32 ratio). Methods Beginning at age 25 d, 42 G93A mice were provided food ad libitum with either adequate (AI;1 IU D3/g feed; 12 M, 11 F) or deficient (DEF; 0.025 IU D3/g feed; 10 M, 9 F) D3. At age 113 d, the spinal cords were analyzed for protein content. Differences were considered significant at P ≤ 0.10, since this was a pilot study. Results DEF mice had 16% higher 4-HNE (P = 0.056), 12% higher GPx1 (P = 0.057) and 23% higher Bax/Bcl2 ratio (P = 0.076) vs. AI. DEF females had 29% higher GPx1 (P = 0.001) and 22% higher IL-6 (P = 0.077) vs. AI females. DEF males had 23% higher 4-HNE (P = 0.066) and 18% lower SOD2 (P = 0.034) vs. AI males. DEF males had 27% lower SOD2 (P = 0.004), 17% lower GPx1 (P = 0.070), 29% lower IL-6 (P = 0.023) and 22% lower ChAT (P = 0.082) vs. DEF females. Conclusion D3 deficiency exacerbates disease pathophysiology in the spinal cord of G93A mice, the exact mechanisms are sex-specific. This is in accord with our previous results in the quadriceps, as well as functional and disease outcomes.
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Affiliation(s)
- Elnaz Moghimi
- School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada
- Muscle Health Research Centre, York University, Toronto, Ontario, Canada
| | - Jesse A. Solomon
- School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada
- Muscle Health Research Centre, York University, Toronto, Ontario, Canada
| | - Alexandro Gianforcaro
- School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada
- Muscle Health Research Centre, York University, Toronto, Ontario, Canada
| | - Mazen J. Hamadeh
- School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada
- Muscle Health Research Centre, York University, Toronto, Ontario, Canada
- * E-mail:
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Yılmaz T, Kaptanoğlu E. Current and future medical therapeutic strategies for the functional repair of spinal cord injury. World J Orthop 2015; 6:42-55. [PMID: 25621210 PMCID: PMC4303789 DOI: 10.5312/wjo.v6.i1.42] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Spinal cord injury (SCI) leads to social and psychological problems in patients and requires costly treatment and care. In recent years, various pharmacological agents have been tested for acute SCI. Large scale, prospective, randomized, controlled clinical trials have failed to demonstrate marked neurological benefit in contrast to their success in the laboratory. Today, the most important problem is ineffectiveness of nonsurgical treatment choices in human SCI that showed neuroprotective effects in animal studies. Recently, attempted cellular therapy and transplantations are promising. A better understanding of the pathophysiology of SCI started in the early 1980s. Research had been looking at neuroprotection in the 1980s and the first half of 1990s and regeneration studies started in the second half of the 1990s. A number of studies on surgical timing suggest that early surgical intervention is safe and feasible, can improve clinical and neurological outcomes and reduce health care costs, and minimize the secondary damage caused by compression of the spinal cord after trauma. This article reviews current evidence for early surgical decompression and nonsurgical treatment options, including pharmacological and cellular therapy, as the treatment choices for SCI.
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Hu AM, Li JJ, Sun W, Yang DG, Yang ML, Du LJ, Gu R, Gao F, Li J, Chu HY, Zhang X, Gao LJ. Myelotomy reduces spinal cord edema and inhibits aquaporin-4 and aquaporin-9 expression in rats with spinal cord injury. Spinal Cord 2014; 53:98-102. [PMID: 25448191 DOI: 10.1038/sc.2014.209] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2014] [Revised: 10/15/2014] [Accepted: 10/20/2014] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Spinal cord edema contributes to the pathophysiological mechanisms underlying spinal cord injury (SCI) and is associated with functional recovery after SCI. Early myelotomy may be a promising surgical intervention for reducing SCI-induced edema. However, it remains unclear whether myelotomy can reduce SCI-induced edema. In addition, aquaporin-4 (AQP4) and aquaporin-9 (AQP9) have important roles in the regulation of water homeostasis. Here, we aimed to determine the effects of myelotomy on AQP4 and AQP9 expression and spinal cord edema in a rat model of moderate SCI. METHODS Rats were randomly assigned to three groups: the sham control group (n=22) receiving laminectomy alone; the contusion group (n=44) receiving laminectomy plus contusion; and the myelotomy group (n=44) receiving laminectomy plus contusion followed by myelotomy at 24 h. Functional recovery was estimated by the open-field and inclined plane tests. Spinal cord edema was determined by measuring the water content. The expression of AQP4 and AQP9 was determined by western blot. RESULTS Compared with the contusion group, myelotomy significantly improved the Basso, Beattie and Bresnahan scores in the open-field test and resulted in a higher mean angle value in the incline plane test. Myelotomy significantly reduced SCI-induced edema at 4 and 6 days after SCI, which was accompanied by downregulation of AQP4 and AQP9 expression. CONCLUSION Myelotomy improves locomotor function, reduces edema in rats with SCI and is associated with decreased expression of AQP4 and AQP9.
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Affiliation(s)
- A-M Hu
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
| | - J-J Li
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
| | - W Sun
- China Rehabilitation Research Center, Department of Neurosurgery, School of Rehabilitation Medicine of Capital Medical University, Beijing, China
| | - D-G Yang
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
| | - M-L Yang
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
| | - L-J Du
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
| | - R Gu
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
| | - F Gao
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
| | - J Li
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
| | - H-Y Chu
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
| | - X Zhang
- China Rehabilitation Research Center, Department of Neurosurgery, School of Rehabilitation Medicine of Capital Medical University, Beijing, China
| | - L-J Gao
- Capital Medical University School of Rehabilitation Medicine, Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing, China
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Mahmoud MA, Fahmy GH, Moftah MZ, Sabry I. Distribution of nitric oxide-producing cells along spinal cord in urodeles. Front Cell Neurosci 2014; 8:299. [PMID: 25309330 PMCID: PMC4174862 DOI: 10.3389/fncel.2014.00299] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 09/05/2014] [Indexed: 11/24/2022] Open
Abstract
Nitric oxide is a unique neurotransmitter, which participates in many physiological and pathological processes in the organism. There are little data about the neuronal nitric oxide synthase immunoreactivity in the spinal cord of amphibians. In this respect, the present study aims to investigate the distribution of nitric oxide producing cells in the spinal cord of urodele and to find out the possibility of a functional locomotory role to this neurotransmitter. The results of the present study demonstrate a specific pattern of NADPH-d labeling in the selected amphibian model throughout the spinal cord length as NADPH-d-producing cells and fibers were present in almost all segments of the spinal cord of the salamander investigated. However, their number, cytological characteristics and labeling intensity varied significantly. It was noticed that the NO-producing cells (NO-PC) were accumulated in the ventral side of certain segments in the spinal cord corresponding to the brachial and sacral plexuses. In addition, the number of NO-PC was found to be increased also at the beginning of the tail and this could be due to the fact that salamanders are tetrapods having bimodal locomotion, namely swimming and walking.
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Affiliation(s)
- Mayada A Mahmoud
- Faculty of Medicine, Institut de Neurosciences des Systèmes, Unités Mixtes de Recherche Institut National de la Santé et de la Recherche Médicale 1106, Aix-Marseille University Marseille, France
| | - Gehan H Fahmy
- Zoology Department, Faculty of Science, Alexandria University Alexandria, Egypt
| | - Marie Z Moftah
- Zoology Department, Faculty of Science, Alexandria University Alexandria, Egypt
| | - Ismail Sabry
- Zoology Department, Faculty of Science, Alexandria University Alexandria, Egypt
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Lu A, Wagner KR, Broderick JP, Clark JF. Administration of S-methyl-L-thiocitrulline protects against brain injuries after intracerebral hemorrhage. Neuroscience 2014; 270:40-7. [PMID: 24726981 DOI: 10.1016/j.neuroscience.2014.04.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 02/21/2014] [Accepted: 04/02/2014] [Indexed: 11/19/2022]
Abstract
Although intracerebral hemorrhage (ICH) increases the level of glutamate in the perihematomal area and cerebral spinal fluid (CSF) in the ICH acute phase, it is unclear whether elevated glutamate activates neuronal nitric oxide synthase (nNOS) in the ICH brain and whether nNOS is an important target for ICH treatment. Here, we assessed the role of the nNOS inhibitor S-methyl-l-thiocitrulline (SMTC) in the activity of NADPH-d and ICH-induced brain injuries. An autologous blood intracerebral infusion model in male rats was used. All of the rats were sacrificed 24h after ICH. ICH increased NADPH-d activity in the striatum. Administering SMTC 3h after ICH decreased the activity of NADH-d (p<0.05 vs. the ICH group). The activation of gelatinolytic enzymes in the perihematomal region of the striatum was reduced by SMTC treatment (p<0.01, vs. the ICH group). The loss of laminin- and occludin-stained vessels was significant in perihematomal regions after 24h of ICH and was significantly attenuated by the administration of SMTC (p<0.01 for laminin, p<0.05 for occluding, compared with the ICH group). Neuronal death and neurological deficits after ICH were also decreased in SMTC treatment rats (p<0.01, vs. the ICH group). The results suggest that the administration of the nNOS inhibitor SMTC after ICH protects against ICH-induced brain injuries and improves neurological function.
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Affiliation(s)
- A Lu
- Department of Neurology, University of Cincinnati, Cincinnati, OH 45267-0532, USA.
| | - K R Wagner
- Department of Neurology, University of Cincinnati, Cincinnati, OH 45267-0532, USA
| | - J P Broderick
- Department of Neurology, University of Cincinnati, Cincinnati, OH 45267-0532, USA
| | - J F Clark
- Department of Neurology, University of Cincinnati, Cincinnati, OH 45267-0532, USA
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Anti-inflammatory effects of curcumin in experimental spinal cord injury in rats. Inflamm Res 2014; 63:381-7. [DOI: 10.1007/s00011-014-0710-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2013] [Revised: 12/17/2013] [Accepted: 01/12/2014] [Indexed: 01/19/2023] Open
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Size- and age-dependent neurotoxicity of engineered metal nanoparticles in rats. Mol Neurobiol 2013; 48:386-96. [PMID: 23821031 DOI: 10.1007/s12035-013-8500-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 06/19/2013] [Indexed: 01/02/2023]
Abstract
Earlier we showed that chronic administration of engineered nanoparticles (NPs) from metals, e.g., Cu, Ag, or Al (50-60 nm, 50 mg/kg, i.p. daily for 1 week) alter blood-brain barrier (BBB) disruption and induce brain pathology in adult rats (age 18 to 22 weeks). However, effects of size-dependent neurotoxicity of NPs in vivo are still largely unknown. In present investigation, we examined the effects of different size ranges of the above-engineered NPs on brain pathology in rats. Furthermore, the fact that age is also an important factor in brain pathology was also investigated in our rat model. Our results showed that small-sized NPs induced the most pronounced BBB breakdown (EBA +480 to 680 %; radioiodine +850 to 1025 %), brain edema formation (+4 to 6 %) and neuronal injuries (+30 to 40 %), glial fibrillary acidic protein upregulation (+40 to 56 % increase), and myelin vesiculation (+30 to 35 % damage) in young animals as compared to controls. Interestingly, the oldest animals (30 to 35 weeks of age) also showed massive brain pathology as compared to young adults (18 to 20 weeks old). The Ag and Cu exhibited greater brain damage compared with Al NPs in all age groups regardless of their size. This suggests that apart from the size, the composition of NPs is also important in neurotoxicity. The very young and elderly age groups exhibited greater neurotoxicity to NPs suggests that children and elderly are more vulnerable to NPs-induced brain damage. The NPs-induced brain damage correlated well with the upregulation of neuronal nitric oxide synthase activity in the brain indicating that NPs-induced neurotoxicity may be mediated via increased production of nitric oxide, not reported earlier.
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Hyun SJ, Lee CH, Kwon JW, Yoon CY, Lim JY, Kim KJ, Jahng TA, Kim HJ. Comparative analysis between thoracic spinal cord and sacral neuromodulation in a rat spinal cord injury model: a preliminary report of a rat spinal cord stimulation model. KOREAN JOURNAL OF SPINE 2013; 10:14-8. [PMID: 24757451 PMCID: PMC3941736 DOI: 10.14245/kjs.2013.10.1.14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Revised: 02/23/2013] [Accepted: 03/13/2013] [Indexed: 11/19/2022]
Abstract
Objective The purpose of this study is to compare a neuroprotective effect of thoracic cord neuromodulation to that of sacral nerve neuromodulation in rat thoracic spinal cord injury (SCI) model. Methods Twenty female Sprague Dawley rats were randomly divided into 4 groups: the normal control group (n=5), SCI with sham stimulation group (SCI, n=5), SCI with electrical stimulation at thoracic spinal cord (SCI + TES, n=5), and SCI with electrical stimulation at sacral nerve (SCI + SES, n=5). Spinal cord was injured by an impactor which dropped from 25mm height. Electrical stimulation was performed by the following protocol: pulse duration, 0.1ms; frequency, 20 Hz; stimulation time, 30 minutes; and stimulation duration at thoracic epidural space and S2 or 3 neural foramina for 4 weeks. Locomotor function, urodynamic study, muscle weights, and fiber cross sectional area (CSA) were investigated. Results All rats of the SCI + TES group expired within 3 days after the injury. The locomotor function of all survived rats improved over time but there was no significant difference between the SCI and the SCI + SES group. All rats experienced urinary retention after the injury and recovered self-voiding after 3-9 days. Voiding contraction interval was 25.5±7.5 minutes in the SCI group, 16.5±5.3 minutes in the SCI+SES group, and 12.5±4.2 minutes in the control group. The recovery of voiding contraction interval was significant in the SCI + SES group comparing to the SCI group (p<0.05). Muscle weight and CSA were slightly greater in the SCI + SES than in the SCI group, but the difference was not significant. Conclusion We failed to establish a rat spinal cord stimulation model. However, sacral neuromodulation have a therapeutic potential to improve neurogenic bladder and muscle atrophy.
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Affiliation(s)
- Seung-Jae Hyun
- Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Chang-Hyun Lee
- Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Ji Woong Kwon
- Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Cheol-Yong Yoon
- Department of Urology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Jae-Young Lim
- Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Ki-Jeong Kim
- Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Tae-Ahn Jahng
- Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hyun-Jib Kim
- Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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Lee CH, Hyun SJ, Yoon CY, Lim JY, Jahng TA, Kim KJ. Neuroprotective effects of sacral epidural neuromodulation following spinal cord injury : an experimental study in rats. J Korean Neurosurg Soc 2012; 52:509-12. [PMID: 23346320 PMCID: PMC3550416 DOI: 10.3340/jkns.2012.52.6.509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2012] [Revised: 10/25/2012] [Accepted: 12/18/2012] [Indexed: 11/27/2022] Open
Abstract
Objective The purpose of this study is to evaluate neuroprotective effect of sacral neuromodulation in rat spinal cord injury (SCI) model in the histological and functional aspects. Methods Twenty-one female Sprague Dawley rats were randomly divided into 3 groups : the normal control group (CTL, n=7), the SCI with sham stimulation group (SCI, n=7), and the SCI with electrical stimulation (SCI+ES, n=7). Spinal cord was injured by dropping an impactor from 25 mm height. Sacral nerve electrical stimulation was performed by the following protocol : pulse duration, 0.1 ms; frequency, 20 Hz; stimulation time, 30 minutes; and stimulation duration, 4 weeks. Both locomotor function and histological examination were evaluated as scheduled. Results The number of anterior horn cell was 12.3±5.7 cells/high power field (HPF) in the CTL group, 7.8±4.9 cells/HPF in the SCI group, and 6.9±5.5 cells/HPF in the SCI+ES group, respectively. Both the SCI and the SCI+ES groups showed severe loss of anterior horn cells and myelin fibers compared with the CTL group. Cavitation and demyelinization of the nerve fibers has no significant difference between the SCI group and the SCI+ES group. Cavitation of dorsal column was more evident in only two rats of SCI group than the SCI+ES group. The locomotor function of all rats improved over time but there was no significant difference at any point in time between the SCI and the SCI+ES group. Conclusion In a rat thoracic spinal cord contusion model, we observed that sacral neuromodulation did not prevent SCI-induced myelin loss and apoptosis.
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Affiliation(s)
- Chang-Hyun Lee
- Department of Neurosurgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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Ghobrial GM, Dalyai R, Flanders AE, Harrop J. Nitrous oxide myelopathy posing as spinal cord injury. J Neurosurg Spine 2012; 16:489-91. [DOI: 10.3171/2012.2.spine11532] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The authors describe a patient who presented with acute tetraparesis and a proposed acute traumatic spinal cord injury that was the result of nitrous oxide myelopathy. This 19-year-old man sustained a traumatic fall off a 6-ft high wall. His examination was consistent with a central cord syndrome with the addition of dorsal column impairment. Cervical MRI demonstrated an isolated dorsal column signal that was suggestive of a nontraumatic etiology. The patient's symptoms resolved entirely over the course of 48 hours.
Nitrous oxide abuse is increasing in prevalence. Its toxic side effects can mask vitamin B12 and folate deficiency and central cord syndrome. The patient's history and radiographic presentation are key to establishing a diagnosis.
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Schomberg D, Olson JK. Immune responses of microglia in the spinal cord: Contribution to pain states. Exp Neurol 2012; 234:262-70. [DOI: 10.1016/j.expneurol.2011.12.021] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Revised: 12/05/2011] [Accepted: 12/13/2011] [Indexed: 01/24/2023]
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Mao L, Wang H, Wang X, Liao H, Zhao X. Transcription factor Nrf2 protects the spinal cord from inflammation produced by spinal cord injury. J Surg Res 2011; 170:e105-15. [PMID: 21764072 DOI: 10.1016/j.jss.2011.05.049] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Revised: 05/15/2011] [Accepted: 05/25/2011] [Indexed: 10/18/2022]
Abstract
BACKGROUND Inflammation plays an important role in the pathogenesis of secondary damage after spinal cord injury (SCI). Previous studies have suggested that nuclear factor-erythroid 2-related factor 2 (Nrf2), a pleiotropic transcription factor, may play a key role in modulating inflammation in a variety of experimental models. This study evaluated the neuroprotective role of Nrf2 in the inflammatory response after SCI in mice. MATERIALS AND METHODS Nrf2-deficient (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mice spinal cord compression injury was induced by the application of vascular clips (force of 10 g) to the dura. Sulforaphane (SFN) was used to activate Nrf2 after SCI. Inflammatory cytokines, NF-κB activity, histologic injury score, dying neurons count in grey matter, water content of impaired spinal cord, and Basso open-field motor score (BMS) were assessed to determine the extent of SCI-mediated damage. RESULTS The results showed that SFN activated Nrf2 in impaired spinal cord tissue, improved hindlimb locomotor function assessed by BMS, reduced inflammatory damage, histologic injury, dying neurons count, and spinal cord edema caused by SCI. Nrf2(-/-) mice demonstrated more severe neurologic deficit and spinal cord edema after SCI and did not benefit from the protective effect of SFN. CONCLUSIONS Taken together, our results suggest that Nrf2 may represent a strategic target for SCI therapies.
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Affiliation(s)
- Lei Mao
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, PR China
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Yeo SI, Ryu HJ, Kim JE, Chun W, Seo CH, Lee BC, Choi IG, Sheen SH, Kang TC. The effects of electrical shock on the expressions of aquaporin subunits in the rat spinal cords. Anat Cell Biol 2011; 44:50-9. [PMID: 21519549 PMCID: PMC3080008 DOI: 10.5115/acb.2011.44.1.50] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2010] [Revised: 12/22/2010] [Accepted: 12/27/2010] [Indexed: 11/27/2022] Open
Abstract
We analyzed aquaporin (AQP) expression in the rat spinal cord following an electrical shock (ES) to elucidate the roles of AQP in spinal cord injury (SCI) induced by an electrical burn. In control animals, AQP1 immunoreactivity was observed in the small diameter dorsal horn fibers of laminae I and II and in astrocytes and neurons in the spinal cord. Both AQP4 and AQP9 immunoreactivity were detected in astrocytes. One week after the ES, AQP1 immunoreactivity in dorsal horn fibers was downregulated to 83, 61, and 33% of control levels following a 1-, 4-, or 6-second ES, respectively. However, AQP1 immunoreactivity in ventral horn neurons increased to 1.3-, 1.5-, and 2.4-fold of control levels following a 1-, 4-, or 6-second ES, respectively. AQP4 immunoreactivity was upregulated after an ES in laminae I and II astrocytes in a stimulus-intensity independent manner. Unlike AQP1 and AQP4, AQP9 immunoreactivity was unaffected by the ES. These findings indicate that altered AQP immunoreactivity may be involved in SCI following an ES.
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Affiliation(s)
- Seong-Il Yeo
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon, Korea
- Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, Korea
| | - Hea Jin Ryu
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon, Korea
- Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, Korea
| | - Ji-Eun Kim
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon, Korea
- Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, Korea
| | - Wook Chun
- Department of Surgery, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
| | - Cheong Hoon Seo
- Department of Rehabilitation, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
| | - Boung Chul Lee
- Department of Psychiatry, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
| | - Ihn-Geun Choi
- Department of Psychiatry, Hangang Sacred Heart Hospital, College of Medicine, Hallym University, Seoul, Korea
| | - Seung Hun Sheen
- Department of Neurosurgery, Graduate School, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Tae-Cheon Kang
- Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chuncheon, Korea
- Institute of Epilepsy Research, College of Medicine, Hallym University, Chuncheon, Korea
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Mao L, Wang HD, Pan H, Qiao L. Sulphoraphane enhances aquaporin-4 expression and decreases spinal cord oedema following spinal cord injury. Brain Inj 2011; 25:300-6. [PMID: 21280976 DOI: 10.3109/02699052.2010.542432] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
BACKGROUND Aquaporin-4 (AQP4) is a water channel protein and it is an important determinant of outcome after brain injury. Sulphoraphane (SFN) increases AQP4 levels with reduction of brain oedema at 3 days post-traumatic brain injury. However, little is known about the effect of SFN on AQP4 expression and oedema after spinal cord injury (SCI). METHODS AND PROCEDURES The present study used a murine SCI model induced by compression injury. AQP4 protein level and mRNA level were detected by Western blot and by RT-PCR at 48 hours after SCI, respectively. In addition, immunohistochemical study was used to show AQP4 expression in the spinal cord segments and water content of the spinal cord segments were measured by wet?:?dry weight ratio. MAIN OUTCOMES AND RESULTS This study shows that AQP4 level was decreased in the injured spinal cord segments at 48 hours following SCI. Post-injury administration of SFN increased AQP4 levels, which was accompanied by a significant reduction in spinal cord segment oedema at 48 hours post-injury. CONCLUSION These findings suggest that the reduction of spinal cord oedema in response to SFN administration could be due, in part, to water clearance by AQP4 from the injured spinal cord segments.
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Affiliation(s)
- Lei Mao
- Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, PR China
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Early microvascular reactions and blood-spinal cord barrier disruption are instrumental in pathophysiology of spinal cord injury and repair: novel therapeutic strategies including nanowired drug delivery to enhance neuroprotection. J Neural Transm (Vienna) 2010; 118:155-76. [PMID: 21161717 DOI: 10.1007/s00702-010-0514-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2010] [Accepted: 10/15/2010] [Indexed: 01/19/2023]
Abstract
Spinal cord injury (SCI) is a devastating disease that leads to permanent disability of victims for which no suitable therapeutic intervention has been achieved so far. Thus, exploration of novel therapeutic agents and nano-drug delivery to enhance neuroprotection after SCI is the need of the hour. Previous research on SCI is largely focused to improve neurological manifestations of the disease while ignoring spinal cord pathological changes. Recent studies from our laboratory have shown that pathological recovery of SCI appears to be well correlated with the improvement of sensory motor functions. Thus, efforts should be made to reduce or minimize spinal cord cell pathology to achieve functional and cellular recovery to enhance the quality of lives of the victims. While treating spinal cord disease, recovery of both neuronal and non-neuronal cells, e.g., endothelia and glial cells are also necessary to maintain a healthy spinal cord function after trauma. This review focuses effects of novel therapeutic strategies on the role of spinal cord microvascular reactions and endothelia cell functions, i.e., blood-spinal cord barrier (BSCB) in SCI and repair mechanisms. Thus, new therapeutic approach to minimize spinal cord pathology after trauma using antibodies to various neurotransmitters and/or drug delivery to the cord directly by topical application to maintain strong localized effects on the injured cells are discussed. In addition, the use of nanowired drugs to affect remote areas of the cord after their application on the injured spinal cord in thwarting the injury process rapidly and to enhance the neuroprotective effects of the parent compounds are also described in the light of current knowledge and our own investigations. It appears that local treatment with new therapeutic agents and nanowired drugs after SCI are needed to enhance neurorepair leading to improved spinal cord cellular functions and the sensory motor performances.
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Oliveira LT, Louzada PR, de Mello FG, Ferreira ST. Amyloid-β decreases nitric oxide production in cultured retinal neurons: a possible mechanism for synaptic dysfunction in Alzheimer's disease? Neurochem Res 2010; 36:163-9. [PMID: 20936504 DOI: 10.1007/s11064-010-0287-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2010] [Indexed: 01/21/2023]
Abstract
The neurotoxicity of the amyloid-β peptide (Aβ) appears to be, at least in part, related to pathological activation of glutamate receptors by Aβ aggregates. However, the downstream signaling pathways leading to neurodegeneration are still incompletely understood. Hyperactivation of nitric oxide synthase (NOS) and increased nitric oxide (NO) production have been implicated in excitotoxic neuronal damage caused by overactivation of glutamate receptors, and it has been suggested that increased NO levels might also play a role in neurotoxicity in Alzheimer's disease. We have examined the effect of blockade of NO production on the neurotoxicity instigated by Aβ₄₂ and by elevated concentrations of glutamate in chick embryo retinal neurons in culture. Results showed that L-nitroarginine methyl ester, a potent inhibitor of all NOS isoforms, had no protective effect against neuronal death induced by either Aβ₄₂ (20 μM) or glutamate (1 mM). Surprisingly, at short incubation times both Aβ and glutamate decreased NO production in retinal neuronal cultures in the absence of neuronal death. Thus, excitotoxic insults induced by Aβ and glutamate cause inhibition rather than activation of NO synthase in retinal neurons, suggesting that cell death induced by Aβ or glutamate is not related to increased NO production. On the other hand, considering the role of NO in long term potentiation and synaptic plasticity, the decrease in NO levels instigated by Aβ and glutamate suggests a possible mechanism leading to synaptic failure in AD.
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Affiliation(s)
- Leandro T Oliveira
- Instituto de Bioquímica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-590, Brazil
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Sharma HS. A combination of tumor necrosis factor-alpha and neuronal nitric oxide synthase antibodies applied topically over the traumatized spinal cord enhances neuroprotection and functional recovery in the rat. Ann N Y Acad Sci 2010; 1199:175-85. [PMID: 20633123 DOI: 10.1111/j.1749-6632.2009.05327.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The possibility that neutralization of nitric oxide synthase and tumor necrosis factor alpha (TNF-alpha) in the cord using their antiserum will induce neuroprotection and improve functional outcome following spinal cord injury (SCI) was examined in a rat model. The SCI was induced in rats by a unilateral incision of the right dorsal horn at the T10-11 segments under equithesin anesthesia. TNF-alpha and/or neuronal nitric oxide synthase (nNOS) antibodies were applied over the traumatized spinal cord at 10-90 minutes after injury and functional recovery and cord pathophysiology were examined at five hours. Topical application of TNF-alpha antiserum at 10 min followed by NOS antiserum at 20 min after SCI significantly improved functional recovery and attenuated blood-spinal cord barrier (BSCB) disturbances, edema formation, and cord pathology. These neuroprotective effects were also seen when the NOS antiserum was applied 10 min after injury followed by TNF-alpha antiserum at 30 min after trauma. However, when TNF-alpha antiserum was applied 1 h after injury and NOS antiserum was given either before or after TNF-alpha antiserum, no neuroprotective effects were observed. Interestingly, neuronal injury was tightly correlated with nNOS expression in the cord in antibody treated groups. These novel observations suggest that early blockade of TNF-alpha and nNOS expression within 20-30 min after SCI is beneficial in nature. This indicates that TNF-alpha and nitric oxide play synergistic roles in the pathophysiology of SCI and combined antibodies therapy has added neuroprotective values in spinal trauma.
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Affiliation(s)
- Hari Shanker Sharma
- Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology and Intensive Care Medicine, University Hospital, Uppsala University, Uppsala, Sweden.
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Kohgami S, Ogata T, Morino T, Yamamoto H, Schubert P. Pharmacological shift of the ambiguous nitric oxide action from neurotoxicity to cyclic GMP-mediated protection. Neurol Res 2010; 32:938-44. [PMID: 20426899 DOI: 10.1179/016164110x12681290831243] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
OBJECTIVES The effect of intracellular cyclic guanosine monophosphate (GMP) increase on neuronal damage was tested using a newly developed nitric oxide-related injury model of cultured spinal cord neurons. METHODS Neuronal damage after 24-hour-exposure to sodium nitroprusside (SNP), a nitric oxide (NO) donor, was evaluated by measuring the activity of released lactate dehydrogenase from injured neurons. RESULTS Oxygen radical scavengers had a protective effect, indicating that the neuronal damage, elicited by 10 μM SNP, was largely due to peroxynitrite formation. Alternatively, a strong inhibition of the NO-induced damage could also be achieved by an intracellular cyclic GMP increase resulting from the addition of 100 μM 8-bromo-cyclic GMP. Propentofylline (PPF, 1-100 μM), a xanthine derivative and rather selective phosphodiesterase (PDE) inhibitor, enhanced intracellular cyclic GMP elevation induced by SNP exposure. The neuronal damage induced by 10 μM SNP exposure for 24 hours was almost completely blocked in the presence of 1 μM PPF. DISCUSSION These results suggest that NO has an ambiguous action, i.e. toxic by favoring the formation of, but protective by intracellular cyclic GMP elevation which can be reinforced by PDE inhibition. Therefore, PDE inhibitors, such as PPF, may be useful therapeutic drugs to limit oxidative neuronal damage in the central nervous system.
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Possible involvement of NO/NOS signaling in hippocampal amyloid-β production induced by transient focal cerebral ischemia in aged rats. Neurosci Lett 2010; 470:106-10. [DOI: 10.1016/j.neulet.2009.12.064] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Revised: 12/13/2009] [Accepted: 12/22/2009] [Indexed: 11/22/2022]
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Saadoun S, Papadopoulos MC. Aquaporin-4 in brain and spinal cord oedema. Neuroscience 2009; 168:1036-46. [PMID: 19682555 DOI: 10.1016/j.neuroscience.2009.08.019] [Citation(s) in RCA: 140] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2009] [Revised: 07/28/2009] [Accepted: 08/07/2009] [Indexed: 02/02/2023]
Abstract
Brain oedema is a major clinical problem produced by CNS diseases (e.g. stroke, brain tumour, brain abscess) and systemic diseases that secondarily affect the CNS (e.g. hyponatraemia, liver failure). The swollen brain is compressed against the surrounding dura and skull, which causes the intracranial pressure to rise, leading to brain ischaemia, herniation, and ultimately death. A water channel protein, aquaporin-4 (AQP4), is found in astrocyte foot processes (blood-brain border), the glia limitans (subarachnoid cerebrospinal fluid-brain border) and ependyma (ventricular cerebrospinal fluid-brain border). Experiments using mice lacking AQP4 or alpha syntrophin (which secondarily downregulate AQP4) showed that AQP4 facilitates oedema formation in diseases causing cytotoxic (cell swelling) oedema such as cerebral ischaemia, hyponatraemia and meningitis. In contrast, AQP4 facilitates oedema elimination in diseases causing vasogenic (vessel leak) oedema and therefore AQP4 deletion aggravates brain oedema produced by brain tumour and brain abscess. AQP4 is also important in spinal cord oedema. AQP4 deletion was associated with less cord oedema and improved outcome after compression spinal cord injury in mice. Here we consider the possible routes of oedema formation and elimination in the injured cord and speculate about the role of AQP4. Finally we discuss the role of AQP4 in neuromyelitis optica (NMO), an inflammatory demyelinating disease that produces oedema in the spinal cord and optic nerves. NMO patients have circulating AQP4 IgG autoantibody, which is now used for diagnosing NMO. We speculate how NMO-IgG might produce CNS inflammation, demyelination and oedema. Since AQP4 plays a key role in the pathogenesis of CNS oedema, we conclude that AQP4 inhibitors and activators may reduce CNS oedema in many diseases.
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Affiliation(s)
- S Saadoun
- Academic Neurosurgery Unit, St George's University of London, London SW17 0RE, UK
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Lee MY, Chen L, Toborek M. Nicotine attenuates iNOS expression and contributes to neuroprotection in a compressive model of spinal cord injury. J Neurosci Res 2009; 87:937-47. [DOI: 10.1002/jnr.21901] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Shen LF, Cheng H, Tsai MC, Kuo HS, Chak KF. PAL31 may play an important role as inflammatory modulator in the repair process of the spinal cord injury rat. J Neurochem 2009; 108:1187-97. [DOI: 10.1111/j.1471-4159.2008.05865.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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47
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Bradykinin preconditioning modulates aquaporin-4 expression after spinal cord ischemic injury in rats. Brain Res 2008; 1246:11-8. [DOI: 10.1016/j.brainres.2008.09.087] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2008] [Revised: 09/03/2008] [Accepted: 09/24/2008] [Indexed: 11/18/2022]
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48
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Activation of endothelial nitric oxide synthase following spinal cord injury in mice. Neurosci Lett 2008; 436:265-8. [DOI: 10.1016/j.neulet.2008.03.039] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2008] [Revised: 03/02/2008] [Accepted: 03/15/2008] [Indexed: 01/02/2023]
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Sharma HS, Ali SF, Dong W, Tian ZR, Patnaik R, Patnaik S, Sharma A, Boman A, Lek P, Seifert E, Lundstedt T. Drug delivery to the spinal cord tagged with nanowire enhances neuroprotective efficacy and functional recovery following trauma to the rat spinal cord. Ann N Y Acad Sci 2008; 1122:197-218. [PMID: 18077574 DOI: 10.1196/annals.1403.014] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The possibility that drugs attached to innocuous nanowires enhance their delivery within the central nervous system (CNS) and thereby increase their therapeutic efficacy was examined in a rat model of spinal cord injury (SCI). Three compounds--AP173 (SCI-1), AP713 (SCI-2), and AP364 (SCI-5) (Acure Pharma, Uppsala, Sweden)--were tagged with TiO(2)-based nanowires using standard procedure. Normal compounds were used for comparison. SCI was produced by making a longitudinal incision into the right dorsal horn of the T10-T11 segments under Equithesin anesthesia. The compounds, either alone or tagged with nanowires, were applied topically within 5 to 10 min after SCI. In these rats, behavioral outcome, blood-spinal cord barrier (BSCB) permeability, edema formation, and cell injury were examined at 5 h after injury. Topical application of normal compounds in high quantity (10 microg in 20 microL) attenuated behavioral dysfunction (3 h after trauma), edema formation, and cell injury, as well as reducing BSCB permeability to Evans blue albumin and (131)I. These beneficial effects are most pronounced with AP713 (SCI-2) treatment. Interestingly, when these compounds were administered in identical conditions after tagging with nanowires, their beneficial effects on functional recovery and spinal cord pathology were further enhanced. However, topical administration of nanowires alone did not influence trauma-induced spinal cord pathology or motor functions. Taken together, our results, probably for the first time, indicate that drug delivery and therapeutic efficacy are enhanced when the compounds are administered with nanowires.
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Affiliation(s)
- Hari Shanker Sharma
- Department of Surgical Sciences, University Hospital, Uppsala University, SE-75421 Uppsala, Sweden.
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Cheng C, Li X, Gao S, Niu S, Chen M, Qin J, Guo Z, Zhao J, Shen A. Expression of CAPON after spinal cord injury in rats. J Mol Neurosci 2007; 34:109-19. [PMID: 18074109 DOI: 10.1007/s12031-007-9019-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2007] [Accepted: 07/16/2007] [Indexed: 12/21/2022]
Abstract
The adaptor protein, carboxy-terminal PDZ ligand of nNOS (CAPON), regulates the distribution of neuronal nitric oxide synthase (nNOS) that increased after spinal cord injury (SCI) and produces the key signaling molecule nitric oxide (NO). But little is known about the role of CAPON in the pathological process of SCI. The main objective of the present study was to investigate expression of CAPON and nNOS in a spinal cord contusion model in adult rats. Real time-polymerase chain reaction (PCR) and Western blot analysis revealed that mRNA and protein for CAPON increased at 2 h after SCI and reached the peak at 8 h, gradually recovered to the baseline level at 14 days. The expression of nNOS mRNA and protein was similar to that of CAPON. During the peak expression, CAPON mRNA was found in the ventral horn, mediate zone, dorsal horn, and white matter by in situ hybridization. Immunofluorescence showed that CAPON was colocalized with nNOS in neurons, oligodendrocytes, and some astrocytes of spinal cord tissues within 5 mm from the epicenter. Interaction between CAPON and nNOS was also detected by co-immunoprecipitation. Thus, the transient expression of high levels of CAPON may provide new insight into the secondary response after SCI.
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Affiliation(s)
- Chun Cheng
- The Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, 19 Qi-xiu Road, Nantong, Jiangsu 226001, China
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