title: GSNO promotes functional recovery in experimental TBI by stabilizing HIF-1α.
abstract: Traumatic brain injury (TBI) causes sustained disability due to compromised neurorepair mechanisms. Crucial to neurorepair and functional recovery following both TBI and stroke is hypoxia-inducible factor-1 alpha (HIF-1α). Based on reports that HIF-1α could be stabilized via S-nitrosylation, we tested the hypothesis that the S-nitrosylating agent S-nitrosoglutathione (GSNO) would stabilize HIF-1α, thereby stimulating neurorepair mechanisms and aiding in functional recovery. TBI was induced by controlled cortical impact (CCI) in adult rats. GSNO (0.05mg/kg) was administered at two hours after CCI. The treatment was repeated daily until the 14th day after CCI. Functional recovery was assessed by motor and cognitive functions, and the recovery was compared with the expression of HIF-1α. The mechanisms of GSNO-mediated S-nitrosylation of HIF-1α were determined using brain endothelial cells. While non-treated TBI animals showed sustained neurobehavioral deficits, GSNO treatment of TBI improved neurobehavioral functions. GSNO also increased the expression of HIF-1α and VEGF. The beneficial effects of GSNO on neurobehavioral functions in TBI animals were blocked by treatment with the HIF-1α inhibitor 2-methoxyestradiol (2-ME). The stimulatory effect of GSNO on VEGF was reversed not only by 2-ME but also by the denitrosylating agent dithiothreitol, confirming our hypothesis that GSNO's benefits are mediated by the stabilization of HIF-1α via S-nitrosylation. GSNO's S-nitrosylation of HIF-1α was further confirmed using a biotin switch assay in endothelial cells. The data provide evidence that GSNO treatment of TBI aids functional recovery through stabilizing HIF-1α via S-nitrosylation. GSNO is a natural component of the human brain/body, and its exogenous administration has not shown adverse effects in humans. Therefore, the translational potential of GSNO therapy in TBI is high.
authors: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States. Electronic address: khanm@musc.edu.
authors: Mushfiquddin
authors: M
authors: Khan
authors: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States. Electronic address: Dhammu@musc.edu.
authors: Tajinder S
authors: TS
authors: Dhammu
authors: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States. Electronic address: baarine@musc.edu.
authors: Mauhamad
authors: M
authors: Baarine
authors: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States. Electronic address: kimji@musc.edu.
authors: Jinsu
authors: J
authors: Kim
authors: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States. Electronic address: kaurm@musc.edu.
authors: Manjeet K
authors: MK
authors: Paintlia
authors: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States. Electronic address: singhi@musc.edu.
authors: Inderjit
authors: I
authors: Singh
authors: 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: Avtar K
authors: AK
authors: Singh
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D055550:Protein Stability / Q000187:drug effects; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D026422:S-Nitrosoglutathione / Q000494:pharmacology*
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D026422:S-Nitrosoglutathione
keywords: GSNO; HIF-1α; Neurobehavioral function; Neurorepair; S-nitrosylation; TBI; VEGF