Effects Of Early Constraint-Induced Movement Therapy Combines With Fasudil In Rats Following Acute Ischemic Stroke

Objective:Constraint-induced movement therapy (CIMT) is one of the most promising techniques for the recovery of upper extremity movement in chronic stroke patient. However, its effects on acute stroke has not been confirmed. Some experimental studies in animal models suggest that very early CIMT may not be helpful. Myelin-associated inhibitors, which have upregulated functions in the acute focal infarction brain, limit axonal regeneration by activating Rho-ROCK pathway. The present study examined whether early CIMT combined with a Rho-ROCK inhibitor Fasudil promotes motor recovery after acute ischemic stroke and further explored whether the interaction is involved with the GAP-43,whose expression reflects axonal regeneration.Methods:Adult rats were trained to perform the skilled forelimb reaching test, followed by middle cerebral artery ischemia-reperfusion to impair the preferred forelimb. Rats were assigned to one of3treatment groups (n=9each)(Fasudil+early CIMT, Fasudil only, early CIMT only) and Control group (no treatment). Therapeutic treatments were initiated1day postinfarct and lasted for14days, including intraperitoneal infusion of Fasudil and/or early CIMT,. Behavioral assessments on skilled-reach test and foot-fault test were conducted before the infarct and for4weeks postinfarct respectively.The infarct volumes were calculated by TTC staining for all groups28day postinfarct, moreover,the expression of GAP-43in the peri-ischemia cortex of the four groups were also evaluated at the14th day postinfarct by western blot.Results:(1) All rats showed similar forelimb impairment before treatment. Fasudil alone and in either combination with CIMT facilitated recovery after2weeks of treatment, whereas CIMT alone failed to enhance recovery. Rats in Fasudil+CIMT group demonstrated better forelimb function on skilled-reach and foot-fault test than Fasudil group at Weeks2and4. Infarct sizes and remaining cortical tissue did not differ in the various treatment groups.(2)Fasudil group and combined therapy group improved the level of GAP-43compared with the Control group after2weeks of treatment, while early CIMT group alone failed to elevate the level of GAP-43Rats in Fasudil+CIMT group demonstrated better expression of GAP-43compared with other groups.Conclusions:These results indicate that early CIMT combined with Fasudil, but not CIMT alone promotes motor recovery after acute ischemic stroke,and the positive interaction between early CIMT and Fasudil can not be attributed to the infarct volumes of the rats and may be involved with the protein GAP-43.