Jiang Cheng, Wang Ze-Ning, Kang Yu-Chen, Chen Yi, Lu Wei-Xin, Ren Hai-Jun, Hou Bo-Ru
Department of Neurosurgery, Lanzhou University Second Hospital; Institute of Neurology, Lanzhou University, Lanzhou, Gansu Province, China.
Department of Neurosurgery, Lanzhou University Second Hospital; Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu Province, China.
Neural Regen Res. 2022 Jan;17(1):137-143. doi: 10.4103/1673-5374.314318.
The survival of microglia depends on the colony-stimulating factor-1 receptor (CSF1R) signaling pathway under physiological conditions. Ki20227 is a highly selective CSF1R inhibitor that has been shown to change the morphology of microglia. However, the effects of Ki20227 on the progression of ischemic stroke are unclear. In this study, male C57BL/6 mouse models of focal cerebral ischemic injury were established through the occlusion of the middle cerebral artery and then administered 3 mg/g Ki20227 for 3 successive days. The results revealed that the number of ionized calcium-binding adaptor molecule 1/bromodeoxyuridine double positive cells in the infarct tissue was reduced, the degree of edema was increased, neurological deficits were aggravated, infarct volume was increased, and the number of peri-infarct Nissl bodies was reduced. The number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells in the peri-infarct tissue was increased. The expression levels of Bax and Cleaved caspase-3 were up-regulated. Bcl-2 expression was downregulated. The expression levels of inflammatory factors and oxidative stress-associated factors were increased. These findings suggested that Ki20227 blocked microglial proliferation and aggravated the pathological progression of ischemia/reperfusion injury in a transient middle cerebral artery occlusion model. This study was approved by the Animal Ethics Committee of Lanzhou University Second Hospital (approval No. D2020-68) on March 6, 2020.
在生理条件下，小胶质细胞的存活依赖于集落刺激因子-1受体（CSF1R）信号通路。Ki20227是一种高度选择性的CSF1R抑制剂，已被证明可改变小胶质细胞的形态。然而，Ki20227对缺血性中风进展的影响尚不清楚。在本研究中，通过大脑中动脉闭塞建立雄性C57BL/6小鼠局灶性脑缺血损伤模型，然后连续3天给予3 mg/g Ki20227。结果显示，梗死组织中离子钙结合衔接分子1/溴脱氧尿苷双阳性细胞数量减少，水肿程度增加，神经功能缺损加重，梗死体积增大，梗死周边尼氏体数量减少。梗死周边组织中末端脱氧核苷酸转移酶dUTP缺口末端标记阳性细胞数量增加。Bax和裂解的半胱天冬酶-3的表达水平上调。Bcl-2表达下调。炎症因子和氧化应激相关因子的表达水平增加。这些发现表明，在短暂性大脑中动脉闭塞模型中，Ki20227阻断了小胶质细胞增殖并加重了缺血/再灌注损伤的病理进展。本研究于2020年3月6日获得兰州大学第二医院动物伦理委员会批准（批准号：D2020-68）。
