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GSNO promotes functional recovery in experimental TBI by stabilizing HIF-1α.
- Source :
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Behavioural brain research [Behav Brain Res] 2018 Mar 15; Vol. 340, pp. 63-70. Date of Electronic Publication: 2016 Oct 22. - Publication Year :
- 2018
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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.<br /> (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Brain drug effects
Brain metabolism
Brain pathology
Brain Injuries metabolism
Brain Injuries pathology
Brain Injuries psychology
Cell Line
Disease Models, Animal
Dose-Response Relationship, Drug
Endothelial Cells drug effects
Endothelial Cells metabolism
Endothelial Cells pathology
Gene Expression drug effects
Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors
Male
Mice
Motor Skills drug effects
Motor Skills physiology
Protein Stability drug effects
Random Allocation
Rats, Sprague-Dawley
Recognition, Psychology drug effects
Recognition, Psychology physiology
Recovery of Function physiology
Brain Injuries drug therapy
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Neuroprotective Agents pharmacology
Recovery of Function drug effects
S-Nitrosoglutathione pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1872-7549
- Volume :
- 340
- Database :
- MEDLINE
- Journal :
- Behavioural brain research
- Publication Type :
- Academic Journal
- Accession number :
- 27780722
- Full Text :
- https://doi.org/10.1016/j.bbr.2016.10.037