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.
OBJECTIVE
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.
Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA.
Harutoshi
H
Sakakima
Mushfiquddin
M
Khan
Tajinder S
TS
Dhammu
Anandakumar
A
Shunmugavel
Yoshihiro
Y
Yoshida
Inderjit
I
Singh
Avtar K
AK
Singh
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002867:Chromones / Q000008:administration & dosage; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005081:Exercise Therapy / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000534:rehabilitation*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000008:administration & dosage; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015424:Reperfusion; D026422:S-Nitrosoglutathione / Q000627:therapeutic use*; D012720:Severity of Illness Index; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D002867:Chromones; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D009025:Morpholines; D018696:Neuroprotective Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D026422:S-Nitrosoglutathione; D020813:Receptor, trkB; D051058:Oncogene Protein v-akt; D053148:Caspase 3; D010751:Phosphopyruvate Hydratase