Abstract
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 (KATP) 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 (PGE2). These inhibitory effects of IPT could be reversed by selective mitochondrial KATP (mitoKATP) 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 PGE2. These data strongly suggest that the KATP opener IPT may be a novel and promising neuroprotective drug via inhibiting microglia-mediated neuroinflammation.
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Acknowledgements
This study was partly supported by a grant from the National Natural Science Foundation of China (Nos. 30625038, 30572172, and 30600758), a grant from the Key Project of Natural Science Foundation of Jiangsu Educational Department (Nos. 05KJA31014 and 06KJA31029), a grant from the Key Project of Jiangsu Health Department (No. K200501), and a Specialized Research Fund for the Doctoral Program of Higher Education of China (No. 20040312004).
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Zhou, F., Wu, JY., Sun, XL. et al. Iptakalim Alleviates Rotenone-Induced Degeneration of Dopaminergic Neurons through Inhibiting Microglia-Mediated Neuroinflammation. Neuropsychopharmacol 32, 2570–2580 (2007). https://doi.org/10.1038/sj.npp.1301381
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DOI: https://doi.org/10.1038/sj.npp.1301381
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