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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| Affiliation: | 1. State Key Laboratory for Molecular Biology of Special Economic Animals, Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin 130112, China;2. Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Yantai University, Yantai 264005, China;3. Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China;4. Department of Psychology and Neuroscience, and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO 80309, USA;5. Discipline of Physiology, Adelaide Medical School, University of Adelaide, South Australia, Australia;6. ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, South Australia 5000, Australia;7. School of Pharmaceutical Sciences, Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing 100082, China;8. Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China;1. Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy;2. Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy;3. Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Cagliari, Italy;1. Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, China;2. Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, China;3. State Key Laboratory for Molecular Biology of Special Wild Economic Animals, Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, 130112, China;4. Shemyakin−Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia;5. Department of Biological and Medicinal Physics, Moscow Institute of Physics and Technology, Dolgoprudny, 141701, Russia;6. School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK;7. Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK;1. State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China;2. Beijing Key Laboratory of Diagnostic and Traceability Technologies for Food Poisoning, Beijing Center for Disease Prevention and Control, Beijing 100013, China;3. Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China;4. State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China;5. Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China;1. College of Food Science and Engineering, Jilin Agricultural University, Changchun 130118, China;2. Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China;3. Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China |
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| Abstract: | 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-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. |
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| Keywords: | Toll-like receptor 4 Myeloid differentiation protein 2 Rats Microglia NFkB Proinflammatory cytokines CD11b Allodynia |
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