title: Targeting the nNOS/peroxynitrite/calpain system to confer neuroprotection and aid functional recovery in a mouse model of TBI.
abstract: Traumatic brain injury (TBI) derails nitric oxide (NO)-based anti-inflammatory and anti-excitotoxicity mechanisms. NO is consumed by superoxide to form peroxynitrite, leading to decreased NO bioavailability for S-nitrosoglutathione (GSNO) synthesis and regulation of neuroprotective pathways. Neuronal peroxynitrite is implicated in neuronal loss and functional deficits following TBI. Using a contusion mouse model of TBI, we investigated mechanisms for the opposed roles of GSNO versus peroxynitrite for neuroprotection and functional recovery. TBI was induced by controlled cortical impact (CCI) in adult male mice. GSNO treatment at 2h after CCI decreased the expression levels of phospho neuronal nitric oxide synthase (pnNOS), alpha II spectrin degraded products, and 3-NT, while also decreasing the activities of nNOS and calpains. Treatment of TBI with FeTPPS, a peroxynitrite scavenger, had effects similar to GSNO treatment. GSNO treatment of TBI also reduced neuronal degeneration and improved neurobehavioral function in a two-week TBI study. In a cell free system, SIN-1 (a peroxynitrite donor and 3-nitrotyrosinating agent) increased whereas GSNO (an S-nitrosylating agent) decreased calpain activity, and these activities were reversed by, respectively, FeTPPS and mercuric chloride, a cysteine-NO bond cleaving agent. These data indicate that peroxynitrite-mediated activation and GSNO-mediated inhibition of the deleterious nNOS/calpain system play critical roles in the pathobiology of neuronal protection and functional recovery in TBI disease. Given GSNO׳s safety record in other diseases, its neuroprotective efficacy and promotion of functional recovery in this TBI study make low-dose GSNO a potential candidate for preclinical evaluation.
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States.. Electronic address: khanm@musc.edu.
authors.forename: Mushfiquddin
authors.initials: M
authors.lastname: Khan
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States.. Electronic address: dhammu@musc.edu.
authors.forename: Tajinder S
authors.initials: TS
authors.lastname: Dhammu
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States.; School of Health Science, Kagoshima University, Kagoshima, Japan. Electronic address: fumiyo@health.nop.kagoshima-u.ac.jp.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Matsuda
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States.. Electronic address: annamal@musc.edu.
authors.forename: Balasubramaniam
authors.initials: B
authors.lastname: Annamalai
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States.. Electronic address: dhindsat@musc.edu.
authors.forename: Tejbir Singh
authors.initials: TS
authors.lastname: Dhindsa
authors.affiliation: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States.. Electronic address: singhi@musc.edu.
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States; Ralph H. Johnson VA Medical Center, Charleston, SC, United States. Electronic address: singha@musc.edu.
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D026422:S-Nitrosoglutathione / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D030421:Peroxynitrous Acid; D026422:S-Nitrosoglutathione; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D002154:Calpain; C112682:Capn1 protein, mouse
keywords: Calpain; GSNO; Neurodegeneration; Peroxynitrite; TBI; nNOS