Lovastatin inhibits Toll-like receptor 4 signaling in microglia by targeting its co-receptor myeloid differentiation protein 2 and attenuates neuropathic pain

文献类型： 外文期刊

第一作者： Peng, Yinghua

作者： Peng, Yinghua;Peng, Yinghua;Wang, Xiaohui;Zhang, Xiaozheng;Zhang, Tianshu;Li, Hongyuan;Wang, Yibo;Li, Hang;Chen, Hongqian;Wang, Xiaohui;Grace, Peter M.;Watkins, Linda R.;Grace, Peter M.;Watkins, Linda R.;Hutchinson, Mark R.;Hutchinson, Mark R.;Yin, Hang;Wang, Xiaohui

作者机构：

关键词： Toll-like receptor 4; Myeloid differentiation protein 2; Rats; Microglia; NFkB; Proinflammatory cytokines; CD11b; Allodynia

期刊名称：BRAIN BEHAVIOR AND IMMUNITY （ 影响因子：7.217； 五年影响因子：8.118 ）

ISSN： 0889-1591

年卷期： 2019 年 82 卷

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收录情况： SCI

摘要： There is growing interest in drug repositioning to find new therapeutic indications for drugs already approved for use in people. Lovastatin is an FDA approved drug that has been used clinically for over a decade as a lipid-lowering medication. While lovastatin is classically considered to act as a hydroxymethylglutaryl (HMG)-CoA reductase inhibitor, the present series of studies reveal a novel lovastatin effect, that being as a Toll-like receptor 4 (TLR4) antagonist. Lovastatin selectively inhibits lipopolysaccharide (LPS)-induced TLR4-NF-kappa B activation without affecting signaling by other homologous TLRs. In vitro biophysical binding and cellular thermal shift assay (CETSA) show that lovastatin is recognized by TLR4's coreceptor myeloid differentiation protein 2 (MD-2). This finding is supported by molecular dynamics simulations that lovastatin targets the LPS binding pocket of MD-2 and lovastatin binding stabilizes the MD-2 conformation. In vitro studies of BV-2 microglial cells revealed that lovastatin inhibits multiple effects of LPS, including activation of NFkB; mRNA expression of tumor necrosis factor-a, interleukin-6 and cyclo-oxygenase 2; production of nitric oxide and reactive oxygen species; as well as phagocytic activity. Furthermore, intrathecal delivery of lovastatin over lumbosacral spinal cord of rats attenuated both neuropathic pain from sciatic nerve injury and expression of the microglial activation marker CD11 in lumbar spinal cord dorsal horn. Given the well-established role of microglia and proinflammatory signaling in neuropathic pain, these data are supportive that lovastatin, as a TLR4 antagonist, may be productively repurposed for treating chronic pain.

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