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- W969671572 abstract "INTRODUCTION: Microglia, the resident immune cells of the central nervous system, play a critical role in health and disease. Following injury, microglia upregulate inducible nitric oxide synthase (iNOS), and can exert neurotoxic effects by releasing large quantities of nitric oxide (NO). Expression of iNOS, and many other proinflammatory genes, is regulated in part by Ca2+ influx and Ca2+-dependent transcription factors. The expression of the nonselective cation channel Sur1-Trpm4 may be 1 molecular mechanism by which microglia dynamically modulate Ca2+ influx. We hypothesized that microglial Sur1-Trpm4 plays a role in microglial-mediated neuroinflammation by regulating the calcium-sensitive induction of iNOS. METHODS: The Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) was used as a stimulus to activate microglia. Protein expression was evaluated by immunohistochemistry, Western blot, and coimmunoprecipitation (Co-IP). Quantitative PCR (qPCR) was used to evaluate gene expression. Functional Sur1-Trpm4 activity was evaluated electrophysiologically. Confocal microscopy and the calcium-sensitive fluorescent dye, Fluo-4, was used to dynamically measure intracellular calcium. Extracellular nitrite, a by-product of NO formation, was measured to evaluate iNOS activity. RESULTS: Microglia express functional Sur1-Trpm4 channels, whose activity modulated Ca2+ oscillations induced by TLR4 ligation. Inhibition of Ca2+, Sur1-Trpm4 or NFAT all significantly abrogated the induction of iNOS. The activation of NFAT induced by TLR4 ligation was modulated by inhibition of Sur1. CONCLUSION: Our results strongly support our hypothesis that Sur1-Trpm4 regulates the calcium-sensitive induction of iNOS by controlling NFAT activity. These observations have impactful therapeutic implications. Inhibition of Sur1-Trpm4 using the well-tolerated sulfonylurea glibenclamide (a.k.a. glyburide) may be a promising approach to limit the deleterious effects of microglial-mediated neuroinflammation." @default.
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- W969671572 date "2015-08-01" @default.
- W969671572 modified "2023-09-27" @default.
- W969671572 title "159 Mitigating Microglial-Mediated Neuroinflammation" @default.
- W969671572 doi "https://doi.org/10.1227/01.neu.0000467122.92580.13" @default.
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