Effect of combined treatment with transplantation of BMSCs and an neuroprotective agent,FK506 on enhancement of amelieration of ischemic brain damege.

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Aims : Transplantation of bone marrow stromal cells(BMSCs)has been shown to ameliorate ischemic brain injury in animals. In the present study, we investigated whether the transplantation of BMSCs combined with FK506, a clinically used immunosuppressant, enhanced neuroprotective effects in rat experimental stroke.Methods : Male Sprague-Dawley rats underwent transient 90 min middle cerebral artery occlusion(MCAO). Two or 6 hours after ischemia onset, the rats were randomly assigned to receive intravenous administration of BMSCs plus FK506, BMSCs alone, FK506 alone, or vehicle. Infarct volume, and neurological and immunohistological assessments were performed to examine the effects of these therapies.Results : In 2-hour post-ischemia treatment groups, siginificant improvement of infarct volume and neurological scores were observed 1 day after combination therapy compared with monotherapy, and this neuroprotection continued for 7 days. Combination therapy significantly reduced the number of TUNEL-positive apoptotic cells, increased Bcl-2 expression, decreased Bax expression, and suppressed neutrophil infiltration and microglia/macrophage activation compared to monotherapy. In 6-hour post-ischemia treatment groups, a significant reduction of infarct volume, edema index, and neurological score was observed only in combination therapy group. Moreover, the number of engrafted BMSCs on day 7 with combination therapy was significantly higher than with BMSCs alone.Conclusion : Combination therapy using FK506 enhanced the anti-apoptotic and anti-inflammatory effects of BMSCs and increased the survival of transplanted cells, leading to expansion of the therapeutic time window for BMSCs.