Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation
Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation
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DOI：
10.1038/sj.npp.1301381
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发表时间：
2007-03
影响因子：
7.6
通讯作者：
Fang Zhou;Jiayong Wu;Xiulan Sun;Hong-hong Yao;Jian-hua Ding;G. Hu
中科院分区：
文献类型：
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作者：
Fang Zhou;Jiayong Wu;Xiulan Sun;Hong-hong Yao;Jian-hua Ding;G. Hu
抑制小胶质细胞介导的神经炎症已被认为是治疗帕金森病(PD)等神经退行性疾病的一种有前景的策略。在本研究中，我们证明了全身应用三磷酸腺苷敏感性钾通道开放剂埃他卡林可以减轻鱼藤酮引起的大鼠黑质多巴胺能神经元的变性，并下调小胶质细胞的活化和肿瘤坏死因子α和环氧合酶-2(COX-2)的α水平。在原代培养的大鼠小胶质细胞中，异丙肾上腺素可抑制鱼藤酮诱导的小胶质细胞活化，表现为抑制小胶质细胞阿米巴样形态的改变，降低小胶质细胞活化标志物ED1的表达，减少肿瘤坏死因子α和前列腺素E2(PGE2)的产生。选择性线粒体K-ATP(mitoK-ATP)通道阻断剂5-羟基癸酸(5-HD)可逆转IPT的上述抑制作用。此外，IPT可阻止鱼藤酮诱导的线粒体膜电位降低和小胶质细胞p38/c-jun氨基末端激酶活化，进而调节小胶质细胞的活化和随后产生的肿瘤坏死因子-α和前列腺素E2。
Inhibition of microglia-mediated neuroinflammation has been regarded as a prospective strategy for treating neurodegenerative disorders, such as Parkinson's disease (PD). In the present study, we demonstrated that systematic administration with iptakalim (IPT), an adenosine triphosphate (ATP)-sensitive potassium channel (K ATP) opener, could alleviate rotenone-induced degeneration of dopaminergic neurons in rat substantia nigra along with the downregulation of microglial activation and mRNA levels of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). In rat primary cultured microglia, pretreatment with IPT suppressed rotenone-induced microglial activation evidenced by inhibition of microglial amoeboid morphological alteration, declined expression of ED1 (a marker for activated microglia), and decreased production of TNF-α and prostaglandin E2 (PGE 2). These inhibitory effects of IPT could be reversed by selective mitochondrial K ATP (mitoK ATP) channel blocker 5-hydroxydecanoate (5-HD). Furthermore, pretreatment with IPT prevented rotenone-induced mitochondrial membrane potential loss and p38/c-jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in microglia, which might in turn regulate microglial activation and subsequent production of TNF-α and PGE 2. These data strongly suggest that the K ATP opener IPT may be a novel and promising neuroprotective drug via inhibiting microglia-mediated neuroinflammation.