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

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dc.contributor.authorPeng, Y.
dc.contributor.authorZhang, X.
dc.contributor.authorZhang, T.
dc.contributor.authorGrace, P.M.
dc.contributor.authorLi, H.
dc.contributor.authorWang, Y.
dc.contributor.authorLi, H.
dc.contributor.authorChen, H.
dc.contributor.authorWatkins, L.R.
dc.contributor.authorHutchinson, M.R.
dc.contributor.authorYin, H.
dc.contributor.authorWang, X.
dc.date.issued2019
dc.description.abstractThere 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-κB 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.
dc.description.statementofresponsibilityYinghua Peng, Xiaozheng Zhang, Tianshu Zhang, Peter M. Grace, Hongyuan Li, Yibo Wang, Hang Li, Hongqian Chen, Linda R. Watkins, Mark R. Hutchinson, Hang Yin, Xiaohui Wang
dc.identifier.citationBrain, Behavior, and Immunity, 2019; 82:432-444
dc.identifier.doi10.1016/j.bbi.2019.09.013
dc.identifier.issn0889-1591
dc.identifier.issn1090-2139
dc.identifier.orcidGrace, P.M. [0000-0002-8999-1220]
dc.identifier.orcidHutchinson, M.R. [0000-0003-2154-5950]
dc.identifier.urihttp://hdl.handle.net/2440/122762
dc.language.isoen
dc.publisherElsevier
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1054091
dc.rights© 2019 Elsevier Inc. All rights reserved.
dc.source.urihttps://doi.org/10.1016/j.bbi.2019.09.013
dc.subjectToll-like receptor 4; myeloid differentiation protein 2; rats; microglia; NFkB; proinflammatory cytokines; CD11b; allodynia
dc.titleLovastatin inhibits Toll-like receptor 4 signaling in microglia by targeting its co-receptor myeloid differentiation protein 2 and attenuates neuropathic pain
dc.typeJournal article
pubs.publication-statusPublished

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