Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transient middle cerebral artery occlusion. Decreased miR-7 expression was observed in both young and aged rats of both sexes after cerebral ischemia. Pre- or postischemic treatment with miR-7 mimic decreased the lesion volume in both sexes and ages studied. Furthermore, systemic injection of miR-7 mimic into mice at 30 min (but not 2 hours) after cerebral ischemia substantially decreased the lesion volume and improved motor and cognitive functional recovery with minimal peripheral toxicity. The miR-7 mimic treatment substantially reduced the postischemic induction of α-synuclein (α-Syn), a protein that induces mitochondrial fragmentation, oxidative stress, and autophagy that promote neuronal cell death. Deletion of the gene encoding α-Syn abolished miR-7 mimic-dependent neuroprotection and functional recovery in young male mice. Further analysis confirmed that the transcript encoding α-Syn was bound and repressed by miR-7. Our findings suggest that miR-7 mimics may therapeutically minimize stroke-induced brain damage and disability.

中文翻译：

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microRNA miR-7a-5p 通过抑制 α-突触核蛋白来改善缺血性脑损伤。


缺血性中风是由阻止血液流向大脑的血栓引起的，可能会导致严重残疾，有时甚至致命。我们之前表明，大鼠模型中的短暂局灶性缺血会引起大脑 microRNA 表达的广泛时间变化，并导致 miR-7a-5p (miR-7) 丰度持续下降。在这里，我们根据中风治疗学术行业圆桌会议 (STAIR) 标准评估了 miR-7 模拟寡核苷酸在啮齿类动物脑缺血后的治疗效果。在大脑中动脉短暂闭塞之前或之后，对啮齿类动物进行局部或全身注射 miR-7 模拟物。在脑缺血后，在年轻和老年大鼠中观察到 miR-7 表达下降。缺血前或缺血后使用 miR-7 模拟物治疗可减少所研究的性别和年龄的病变体积。此外，在脑缺血后 30 分钟（但不是 2 小时）向小鼠全身注射 miR-7 模拟物可显着减少病变体积，改善运动和认知功能恢复，同时外周毒性最小。 miR-7 模拟物治疗显着减少了 α-突触核蛋白 (α-Syn) 的缺血后诱导，α-突触核蛋白是一种诱导线粒体断裂、氧化应激和自噬，从而促进神经元细胞死亡的蛋白质。删除编码 α-Syn 的基因会消除年轻雄性小鼠中 miR-7 模拟物依赖性神经保护和功能恢复。进一步分析证实编码 α-Syn 的转录本被 miR-7 结合并抑制。我们的研究结果表明，miR-7 模拟物可以在治疗上最大限度地减少中风引起的脑损伤和残疾。