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

BMSCs移植与神经保护剂FK506联合治疗对改善缺血性脑损伤的增强作用。

基本信息

批准号：
20591011
负责人：
KATAYAMA Yasuo
金额：
$ 2.08万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20591011/
关键词：
脳虚血骨髄細胞移植脳保護薬神経再生神経修復

项目摘要

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.

目的：骨髓基质细胞（BMSCs）移植可改善动物缺血性脑损伤。在本研究中，我们研究了骨髓间充质干细胞与临床使用的免疫抑制剂FK506联合移植是否能增强实验性脑卒中大鼠的神经保护作用。方法：雄性Sprague-Dawley大鼠短暂性大脑中动脉闭塞（MCAO） 90 min。缺血后2小时或6小时，将大鼠随机分为骨髓间充质干细胞加FK506、骨髓间充质干细胞单独、FK506单独或载药组。进行梗死面积、神经学和免疫组织学评估以检查这些治疗的效果。结果：在缺血后2小时治疗组，联合治疗后1天梗死面积和神经学评分明显改善，且这种神经保护持续7天。与单药治疗相比，联合治疗显著减少tunel阳性凋亡细胞数量，增加Bcl-2表达，降低Bax表达，抑制中性粒细胞浸润和小胶质细胞/巨噬细胞活化。在缺血治疗6小时后，只有联合治疗组梗死体积、水肿指数和神经学评分显著降低。此外，联合治疗第7天移植的骨髓间充质干细胞数量明显高于单独治疗。结论：FK506联合治疗可增强骨髓间充质干细胞的抗凋亡和抗炎作用，提高移植细胞的存活率，延长骨髓间充质干细胞的治疗时间窗。