Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
Biochem Biophys Res Commun. 2019 Jul 5;514(4):1040-1044. doi: 10.1016/j.bbrc.2019.05.055. Epub 2019 May 13.
Microglia are immune cells in the central nervous system (CNS) and essential for homeostasis that are important for both neuroprotection and neurotoxicity, and are activated in a variety of CNS diseases. Microglia aggravate cognitive impairment induced by chronic cerebral hypoperfusion, but their precise roles under these conditions remain unknown. Here, we used PLX3397, a colony-stimulating factor 1 receptor inhibitor, to deplete microglia in mice with chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS). Cognitive impairment induced 28 days after BCAS was significantly improved in mice fed a diet containing PLX3397. In PLX3397-fed mice, microglia were depleted and white matter injury induced by BCAS was suppressed. In addition, the expression of proinflammatory cytokines, interleukin 6 and tumor necrosis factor alpha, was suppressed in PLX3397-fed mice. Taken together, these findings suggest that microglia play destructive roles in the development of cognitive impairment and white matter injury induced by chronic cerebral hypoperfusion. Thus, microglia represent a potential therapeutic target for chronic cerebral hypoperfusion-related diseases.
小胶质细胞是中枢神经系统（CNS）中的免疫细胞，对于维持内环境稳定至关重要，它们既具有神经保护作用，也具有神经毒性作用，并在多种中枢神经系统疾病中被激活。小胶质细胞可加重慢性脑低灌注引起的认知障碍，但在这些情况下，其确切作用尚不清楚。在这里，我们使用 PLX3397（一种集落刺激因子 1 受体抑制剂）来耗尽双侧颈总动脉狭窄（BCAS）诱导的慢性脑低灌注小鼠中的小胶质细胞。在喂食含有 PLX3397 的饮食的小鼠中，BCAS 28 天后诱导的认知障碍明显改善。在 PLX3397 喂养的小鼠中，小胶质细胞被耗尽，BCAS 引起的白质损伤受到抑制。此外，PLX3397 喂养的小鼠中促炎细胞因子白细胞介素 6 和肿瘤坏死因子 α 的表达受到抑制。综上所述，这些发现表明小胶质细胞在慢性脑低灌注引起的认知障碍和白质损伤的发展中发挥破坏作用。因此，小胶质细胞可能成为治疗慢性脑低灌注相关疾病的潜在靶点。
