Iptakalim protects against MPP+-induced degeneration of dopaminergic neurons in association with astrocyte activation
Iptakalim protects against MPP+-induced degeneration of dopaminergic neurons in association with astrocyte activation
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Iptakalim 可防止 MPP 诱导的与星形胶质细胞激活相关的多巴胺能神经元变性。
DOI：
10.1017/s1461145708009243
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发表时间：
2009-04-01
影响因子：
4.8
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Yang, Yan-Jing;Zhang, Shu;Hu, Gang
在 MPTP 小鼠模型和帕金森病患者中观察到的星形胶质细胞活化参与了一系列有害事件，最终导致黑质致密部 (SNpc) 中的多巴胺能神经元死亡。本研究旨在阐明抑制星形胶质细胞活化是否与 iptakalim (Ipt)（一种新型 ATP 敏感性钾通道开放剂）对 MPP+ 诱导的多巴胺能神经元变性的保护作用有关。结果表明，Ipt 可以减少 MPP+ 诱导的反应性星形胶质细胞中 TNF-α 的释放和 p38 MAPK 的激活。 Ipt 的作用被线粒体 KATP 阻滞剂 5-羟基癸酸酯逆转，表明线粒体 KATP 通道参与星形胶质细胞激活的调节。此外，系统施用 Ipt 可以显着减轻 MPP+ 诱导的运动协调行为症状、多巴胺能神经元的丧失以及 SNpc 中星形胶质细胞和小胶质细胞的激活。总之，这些发现表明 Ipt 可能通过抑制星形胶质细胞活化和随后促炎因子的释放来防止 MPP+ 诱导的多巴胺能神经元变性。
Astrocyte activation observed in the MPTP mouse model and Parkinson's disease patients participates in the cascade of deleterious events that ultimately leads to death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The present study aimed to elucidate whether inhibiting astrocyte activation was involved in the protective effects of iptakalim (Ipt), a novel ATP-sensitive potassium channel opener, on MPP+-induced degeneration of dopaminergic neurons. The results showed that Ipt could decrease MPP+-induced TNF-alpha release and p38 MAPK activation in reactive astrocytes. The effects of Ipt were reversed by the mitochondrial KATP blocker, 5-hydroxydecanoate, indicating that mitochondrial KATP channels participate in the regulation of astrocyte activation. Moreover, systematic administration of Ipt could significantly alleviate MPP+-induced behavioural symptoms in motor coordination, the loss of dopaminergic neurons, and the activation of astrocyte and microglia in the SNpc. Together, these findings suggest that Ipt may protect against MPP+-induced degeneration of dopaminergic neurons by inhibiting astrocyte activation and subsequent release of pro-inflammatory factors.