Lovastatin inhibits Toll-like receptor 4 signaling in microglia by targeting its co-receptor myeloid differentiation protein 2 and attenuates neuropathic pain
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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洛伐他汀通过靶向其辅助受体骨髓分化蛋白 2 来抑制小胶质细胞中的 Toll 样受体 4 信号传导，并减轻神经性疼痛。
DOI：
10.1016/j.bbi.2019.09.013
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发表时间：
2019-11-01
影响因子：
15.1
通讯作者：
Wang, Xiaohui
中科院分区：
文献类型：
--
作者：
Peng, Yinghua;Zhang, Xiaozheng;Wang, Xiaohui
人们对药物重新定位的兴趣越来越大，以找到新的治疗适应症的药物已经批准用于人。洛伐他汀是FDA批准的药物，已在临床上作为降脂药物使用了十多年。传统上认为洛伐他汀是羟甲基戊二酰（HMG）-CoA还原酶抑制剂，而目前的一系列研究揭示了一种新的洛伐他汀作用，即作为Toll样受体4（TLR4）拮抗剂。洛伐他汀选择性抑制脂多糖（LPS）诱导的TLR4-NF-κ B活化，而不影响其他同源TLR的信号传导。体外生物物理结合和细胞热位移实验（CETSA）表明，洛伐他汀被TLR4的辅助受体髓样分化蛋白2（MD-2）识别。这一发现得到了分子动力学模拟的支持，即洛伐他汀靶向MD-2的LPS结合口袋，并且洛伐他汀结合稳定了MD-2构象。BV-2小胶质细胞的体外研究显示，洛伐他汀抑制LPS的多种作用，包括NF κ B的活化;肿瘤坏死因子-α、白细胞介素-6和环加氧酶2的mRNA表达;一氧化氮和活性氧的产生;以及吞噬活性。此外，通过大鼠腰骶脊髓鞘内注射洛伐他汀可减轻坐骨神经损伤引起的神经病理性疼痛和腰脊髓背角小胶质细胞活化标记物CD 11的表达。考虑到小胶质细胞和促炎信号在神经性疼痛中的作用，这些数据支持洛伐他汀作为TLR4拮抗剂可以有效地用于治疗慢性疼痛。
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.