Ischemia cerebral stroke is one of the common neurological diseases with severe inflammatory response and neuron death. The inhibition of colony-stimulating factor 1 receptor (CSF1R) which especially expressed in microglia/macrophage exerted neuroprotection in stroke. However, the underlying neuroinflammatory regulation effects of CSF1R in ischemia stroke are not clear. In this study, cerebral ischemia stroke mice model was established. The C57/B6J mice were administered with Ki20227, a CSF1R inhibitor, by gavage for 7 consecutive days (0.002 mg/kg/day) before modeling. The Rota-Rod test and neurobehavioral score test were investigated to assess neurobehavioral functions. The area of infarction was assessed by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The mRNA expressions of M1/M2 microglia markers were evaluated by real-time PCR. Immunofluorescence and Western blot were utilized to detect the changes of Iba1 and NLRP3 pathway proteins. Results showed that neurobehavioral function improvement was demonstrated by an increased stay time on the Rota-Rod test and a decreased neurobehavioral score in the Ki20227 treatment group. The area of infarction reduced in Ki20227 group when compared to the stroke group. Moreover, the mRNA expression of M1 microglia markers (TNF-α and iNOS) decreased while M2 microglia markers (IL-10 and Arg-1) increased. Meanwhile, compared to the stroke and stroke+PBS group, Ki20227 administration downregulated the expression of NLRP3, active caspase 1, and NF-κB protein in the ischemia penumbra of Ki20227 treatment group mice. In short, the CSF1R inhibitor, Ki20227, played vital neuroprotective roles in ischemia cerebral stroke mice, and the mechanisms may be via inhibiting microglia M1 polarization and NLRP3 inflammasome pathway activation. Our study provides a potential new target for the treatment of ischemic stroke injury.

中文翻译：

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受抑制的 CSF1R 通过抑制小胶质细胞 M1 极化和 NLRP3 通路减轻缺血损伤。

缺血性脑卒中是常见的神经系统疾病之一，具有严重的炎症反应和神经元死亡。抑制尤其在小胶质细胞/巨噬细胞中表达的集落刺激因子 1 受体 (CSF1R) 在中风中发挥神经保护作用。然而，CSF1R 在缺血性中风中的潜在神经炎症调节作用尚不清楚。本研究建立了脑缺血中风小鼠模型。C57/B6J 小鼠在建模前连续 7 天（0.002 mg/kg/天）通过管饲法给予 Ki20227（一种 CSF1R 抑制剂）。研究了 Rota-Rod 测试和神经行为评分测试以评估神经行为功能。通过 2, 3, 5-三苯基氯化四唑 (TTC) 染色评估梗塞面积。通过实时PCR评估M1/M2小胶质细胞标记物的mRNA表达。采用免疫荧光和Western blot检测Iba1和NLRP3通路蛋白的变化。结果表明，在 Ki20227 治疗组中，通过 Rota-Rod 测试的停留时间增加和神经行为评分降低来证明神经行为功能改善。与卒中组相比，Ki20227 组的梗死面积减少。此外，M1 小胶质细胞标志物（TNF-α和 iNOS）减少，而 M2 小胶质细胞标志物（IL-10 和 Arg-1）增加。同时，相比于中风和中风+ PBS组，Ki20227给药下调NLRP3的表达，活性胱天蛋白酶1，和NF- κ中Ki20227治疗组的小鼠的局部缺血半影B蛋白。总之，CSF1R抑制剂Ki20227在缺血性脑卒中小鼠中发挥重要的神经保护作用，其机制可能是通过抑制小胶质细胞M1极化和NLRP3炎症小体通路激活。我们的研究为缺血性卒中损伤的治疗提供了一个潜在的新靶点。