Qiao Chenmeng, Niu Guyu, Zhao Weijiang, Quan Wei, Zhou Yu, Zhang Meixuan, Li Ting, Zhou Shengyang, Huang Wenyan, Zhao Liping, Wu Jian, Cui Chun, Shen Yanqin
Department of Neurodegeneration and Injury, Wuxi School of Medicine, Jiangnan University, No. 1800, Lihu Avenue, Binhu District, Wuxi 214122, China.
Brain Sci. 2023 Apr 27;13(5):733. doi: 10.3390/brainsci13050733.
Neuroinflammation is one of the hallmarks of Parkinson's disease, including the massive activation of microglia and astrocytes and the release of inflammatory factors. Receptor-interacting protein kinase 1 (RIPK1) is reported to mediate cell death and inflammatory signaling, and is markedly elevated in the brain in PD mouse models. Here, we aim to explore the role of RIPK1 in regulating the neuroinflammation of PD. C57BL/6J mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 20 mg/kg four times/day), followed by necrostatin-1 treatment (Nec-1, RIPK1 inhibitor; 1.65 mg/kg once daily for seven days. Notably, the first Nec-1 was given 12 h before MPTP modeling). Behavioral tests indicated that inhibition of RIPK1 greatly relieved motor dysfunction and anxiety-like behaviors of PD mice. It also increased striatal TH expression, rescue the loss of dopaminergic neurons, and reduce activation of astrocytes in the striatum of PD mice. Furthermore, inhibition of RIPK1 expression reduced A1 astrocytes' relative gene expression (CFB, H2-T23) and inflammatory cytokine or chemokine production (CCL2, TNF-α, IL-1β) in the striatum of PD mice. Collectively, inhibition of RIPK1 expression can provide neuroprotection to PD mice, probably through inhibition of the astrocyte A1 phenotype, and thus RIPK1 might be an important target in PD treatment.
神经炎症是帕金森病的标志性特征之一，包括小胶质细胞和星形胶质细胞的大量激活以及炎症因子的释放。据报道，受体相互作用蛋白激酶1（RIPK1）介导细胞死亡和炎症信号传导，并且在帕金森病小鼠模型的大脑中显著升高。在此，我们旨在探讨RIPK1在调节帕金森病神经炎症中的作用。将C57BL/6J小鼠腹腔注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP；20mg/kg，每天4次），随后进行坏死性凋亡抑制因子-1（Nec-1，RIPK1抑制剂；1.65mg/kg，每天1次，共7天。值得注意的是，第一次给予Nec-1是在MPTP建模前12小时）治疗。行为测试表明，抑制RIPK1可大大缓解帕金森病小鼠的运动功能障碍和焦虑样行为。它还增加了纹状体中酪氨酸羟化酶（TH）的表达，挽救了多巴胺能神经元的损失，并减少了帕金森病小鼠纹状体中星形胶质细胞的激活。此外，抑制RIPK-1表达降低了帕金森病小鼠纹状体中A1星形胶质细胞的相对基因表达（补体因子B（CFB）、组织相容性2类抗原T23（H2-T23））以及炎症细胞因子或趋化因子的产生（趋化因子配体2（CCL2）、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β））。总体而言，抑制RIPK1表达可能通过抑制星形胶质细胞A1表型为帕金森病小鼠提供神经保护，因此RIPK1可能是帕金森病治疗的一个重要靶点。
