Ki20227, a selective inhibitor of colony-stimulating factor 1 receptor (CSF1R), has been suggested to regulate microglia inflammatory function and neuronal synaptic plasticity. Triptolide (TP) pretreatment has neuroprotective effects through its anti-inflammatory and antiapoptotic features in ischemic stroke mice. However, the underlying mechanism and pathway are presently unclear. We thus investigated the association between neuroprotective effects of combined TP and Ki20227 and BDNF-Akt and autophagy pathways. Ki20227 was administrated for 7 days, and TP was administered once 24 hours prior to building the ischemic stroke model in C57BL/6 mice. Behavioral tests, Golgi staining, immunofluorescence, and western blot analyses were employed to examine neuroprotective effects of TP and Ki20227. TP and Ki20227 pretreatments improved the neurobehavioral function in stroke mice. Synaptic protein expressions and density of dendritic spine density were upregulated in Ki20227 and TP pretreated stroke mice. Further, optimized integration of TP and Ki20227 pretreatments upregulated the NeuN expression and downregulated Iba1 expression after stroke. In addition, both TP and Ki20227 pretreatments significantly upregulated BDNF, p-Akt/Akt, and Erk1/2 protein expressions and autophagy related proteins (LC3II/I, Atg5, and p62), indicating the activation of BDNF and autophagic pathways. Optimized integration of TP and Ki20227 can improve cerebral ischemia by inhibiting CSF1R signal and trigger autophagy and BDNF-Akt signaling pathways to increase dendritic spine density and synaptic protein expressions, which in turn enhances neurobehavioral function.

中文翻译：

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集落刺激因子 1 受体抑制剂和雷公藤内酯联合预处理上调 BDNF-Akt 和自噬通路以改善脑缺血

Ki20227 是一种集落刺激因子 1 受体 (CSF1R) 的选择性抑制剂，已被建议调节小胶质细胞炎症功能和神经元突触可塑性。雷公藤内酯 (TP) 预处理通过其在缺血性中风小鼠中的抗炎和抗凋亡特性具有神经保护作用。然而，其潜在机制和途径目前尚不清楚。因此，我们研究了 TP 和 Ki20227 和 BDNF-Akt 组合的神经保护作用与自噬途径之间的关联。Ki20227 给药 7 天，TP 在建立 C57BL/6 小鼠缺血性中风模型前 24 小时给药一次。采用行为测试、高尔基体染色、免疫荧光和蛋白质印迹分析来检查 TP 和 Ki20227 的神经保护作用。TP 和 Ki20227 预处理改善了中风小鼠的神经行为功能。突触蛋白表达和树突棘密度在 Ki20227 和 TP 预处理的中风小鼠中上调。此外，TP 和 Ki20227 预处理的优化整合在中风后上调 NeuN 表达并下调 Iba1 表达。此外，TP 和 Ki20227 预处理均显着上调 BDNF、p-Akt/Akt 和 Erk1/2 蛋白表达和自噬相关蛋白（LC3II/I、Atg5 和 p62），表明 BDNF 和自噬途径的激活。TP 和 Ki20227 的优化整合可以通过抑制 CSF1R 信号并触发自噬和 BDNF-Akt 信号通路来增加树突棘密度和突触蛋白表达来改善脑缺血，从而增强神经行为功能。