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Stimulation of functional recovery via the mechanisms of neurorepair by S-nitrosoglutathione and motor exercise in a rat model of transient cerebral ischemia and reperfusion

Article type: Research Article

Authors: Sakakima, Harutoshi; | Khan, Mushfiquddin | Dhammu, Tajinder S. | Shunmugavel, Anandakumar | Yoshida, Yoshihiro | Singh, Inderjit | Singh, Avtar K.;

Affiliations: Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA | School of Health Science, Kagoshima University, Kagoshima, Japan | Ralph H Johnson VA Medical Center, Charleston, SC, USA | Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA

Note: [] Harutoshi Sakakima and Mushfiquddin Khan contributed equally to this work.

Note: [] Harutoshi Sakakima and Mushfiquddin Khan contributed equally to this work.

Note: [] Corresponding author: Avtar K. Singh, M.D., Professor of Pathology and Laboratory Medicine, Medical University of South Carolina, 508 Children's Research Institute, 173 Ashley Ave, Charleston, SC 29425, USA. Tel.: +1 843 792 7991; Fax: +1 843 792 3653; E-mail: [email protected]

Keywords: GSNO, IR, motor exercise, neurorepair, neurobehavior, rehabilitation, S-nitrosylation, stroke

DOI: 10.3233/RNN-2012-110209

Journal: Restorative Neurology and Neuroscience, vol. 30, no. 5, pp. 383-396, 2012

Published: 2012
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Abstract

Purpose: Stroke disability stems from insufficient neurorepair mechanisms. Improvement of functions has been achieved through rehabilitation or therapeutic agents. Therefore, we combined exercise with a neurovascular protective agent, S-nitrosoglutathione (GSNO), to accelerate functional recovery. Methods: Stroke was induced by middle cerebral artery occlusion for 60 min followed by reperfusion in adult male rats. Animals were treated with vehicle (IR group), GSNO (0.25 mg/kg, GSNO group), rotarod exercise (EX group) and GSNO plus exercise (GSNO+EX group). The groups were studied for 14 days to determine neurorepair mechanisms and functional recovery. Results: Treated groups showed reduced infarction, decreased neuronal cell death, enhanced neurotrophic factors, and improved neurobehavioral functions. However, the GSNO+EX showed greater functional recovery (p < 0.05) than the GSNO or the EX group. A GSNO sub group, treated 24 hours after IR, still showed motor function recovery (p < 0.001). The protective effect of GSNO or exercise was blocked by the inhibition of Akt activity. Conclusions: GSNO and exercise aid functional recovery by stimulating neurorepair mechanisms. The improvements by GSNO and exercise depend mechanistically on the Akt pathway. A combination of exercise and GSNO shows greater functional recovery. Improved recovery with GSNO, even administered 24 hours post-IR, demonstrates its clinical relevance.

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