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Combination therapy with bone marrow stromal cells and FK506 enhanced amelioration of ischemic brain damage in rats.

机译:骨髓基质细胞和FK506的联合治疗可改善大鼠缺血性脑损伤。

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AIMS: Transplantation of bone marrow stromal cells (MSCs) has been shown to ameliorate ischemic brain injury in animals. In the present study, we investigated whether the transplantation of MSCs combined with FK506, a clinically used immunosuppressant, enhanced neuroprotective effects in rat experimental stroke. MAIN METHODS: Male Sprague-Dawley rats underwent transient 90 min middle cerebral artery occlusion (MCAO). Two or 6h after ischemia onset, the rats were randomly assigned to receive intravenous administration of MSCs plus FK506, MSCs alone, FK506 alone, or vehicle. Infarct volume, and neurological and immunohistological assessments were performed to examine the effects of these therapies. KEY FINDINGS: In 2-hour post-ischemia treatment groups, significant 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 the combination therapy group. Moreover, the number of engrafted MSCs on day 7 with combination therapy was significantly higher than with MSCs alone. SIGNIFICANCE: Combination therapy using FK506 enhanced the anti-apoptotic and anti-inflammatory effects of MSCs and increased the survival of transplanted cells, leading to expansion of the therapeutic time window for MSCs.
机译:目的:骨髓基质细胞(MSCs)的移植已被证明可以改善动物的缺血性脑损伤。在本研究中,我们调查了MSCs与临床上使用的免疫抑制剂FK506组合的移植是否增强了大鼠实验性中风的神经保护作用。主要方法:雄性Sprague-Dawley大鼠经历90分钟短暂的大脑中动脉阻塞(MCAO)。缺血发作后2或6小时,将大鼠随机分配为接受MSCs + FK506,单独的MSC,单独的FK506或媒介的静脉内给药。进行梗塞体积以及神经和免疫组织学评估以检查这些疗法的效果。主要发现:在缺血后2小时的治疗组中,与单一疗法相比,联合疗法1天后观察到梗死体积和神经学评分明显改善,并且这种神经保护作用持续了7天。与单一疗法相比,联合疗法可显着减少TUNEL阳性凋亡细胞的数量,增加Bcl-2表达,降低Bax表达,并抑制嗜中性粒细胞浸润和小胶质细胞/巨噬细胞活化。在缺血后6小时治疗组中,仅在联合治疗组中观察到梗塞体积,水肿指数和神经学评分显着降低。而且,在联合治疗的第7天,移植MSC的数量明显高于单独的MSC。意义:FK506联合治疗可增强MSC的抗凋亡和抗炎作用,并增加移植细胞的存活率,从而扩大MSC的治疗时间范围。

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