【罂粟摘要】瑞马唑仑通过调节缓激肽受体B1和自噬减轻神经病理性疼痛

神经性病理性疼痛(NP)是神经系统各种病理分支的广泛代表。


瑞马唑仑通过调节缓激肽受体B1和自噬减轻神经病理性疼痛

翻译:吴学艳  编辑:佟睿  审核:曹莹

贵州医科大学  高鸿教授课题组


目 的

神经性病理性疼痛(NP)是神经系统各种病理分支的广泛代表。瑞马唑仑是一种经证实用于治疗神经性疼痛的镇静剂。由于缓激肽受体的重要作用和缓激肽B1受体抗体(BDKRB1)在神经病理性疼痛信号通路中的潜在作用,我们假设其为瑞马唑仑的主要靶点。


方 法

采本实验采用大鼠体内注射完全弗氏佐剂(CFA)建立NP模型,脂多糖(LPS)处理BV2小胶质细胞,建立体外NP模型。采用qRT -PCR、ELISA、Western blot和免疫荧光等方法检测基因表达。


结 果

研究发现,BDKRB1在体内NP模型中过表达,而R715 (BDKRB1的拮抗剂)抑制了BDKRB1的水平,并抑制脊神经损伤引起的痛觉过敏。此外,瑞马唑仑通过抑制NF-κB转位使BDKRB1信号失活,并减少促炎细胞因子的释放;另外,瑞马唑仑还能抑制NF-κB的转位,并抑制体内、体外自噬溶酶体的形成。然而,R838(BDKRB1的激动剂)逆转了瑞马唑仑的作用。


结 论

瑞马唑仑下调BDKRB1,抑制BDKRB1/RAS/MEK 信号通路和调控自噬溶酶体,在NP治疗中表现出更好的疗效。


原始文献来源

Xie H, Lu F, Liu W, et al.Remimazolam alleviates neuropathic pain via regulating bradykinin receptor B1 and autophagy.[J].J Pharm Pharmacol. 2021 Jun 1:rgab080.


Remimazolam alleviates neuropathic pain via regulating bradykinin receptor B1 and autophagy



Abstract

ObjectivesNeuropathic pain (NP) represents a broad scope of various pathological ramifications of the nervous system. Remimazolam is a proved sedative in treating neuropathic pain. Considering the Bradykinin receptor’s vital role and the potentials of Bradykinin receptor B1 (BDKRB1) in the neuropathic pain-signalling pathway, we nominated them as a primary target for remimazolam.


MethodsIn this study, rats were injected with complete freund’s adjuvant (CFA) to construct NP models in vivo. BV2 microglia cells were treated with LPS to establish NP model in vitro. qRT-PCR, ELISA, western blot and immunofluorescence were applied to determine gene expression.


Key findings: Our findings revealed that BDKRB1 was overexpressed in NP models in vivo, while R715 (an antagonist of BDKRB1) suppressed the levels of BDKRB1 and inhibited the hyperpathia induced by spinal nerve litigation surgery. Moreover, remimazolam inactivated BDKRB1 signalling via suppressing NF-κB translocation and decreased the release of pro-inflammatory cytokines. Additionally, remimazolam suppressed the translocation of NF-κB, and inhibited autophagic lysosome formation in vivo and in vitro. However, R838 (an agonist of BDKRB1) reversed the effects of remimazolam.


Conclusions: Remimazolam downregulated BDKRB1, inhibited BDKRB1/RAS/ MEK signalling pathway and regulated the autophagic lysosome induction, exhibiting a better outcome in the NP.

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