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Metformin attenuates diabetic neuropathic pain via AMPK/NF-κB signaling pathway in dorsal root ganglion of diabetic rats
Brain Research ( IF 2.9 ) Pub Date : 2021-09-20 , DOI: 10.1016/j.brainres.2021.147663
Xiao-Jun Cao 1 , Rui Wu 2 , He-Ya Qian 3 , Xiang Chen 3 , Hong-Yan Zhu 3 , Guang-Yin Xu 2 , Ye-Zi Sun 1 , Ping-An Zhang 2
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Neuropathic pain is a common complication of diabetes mellitus with poorly relieved by conventional analgesics. Metformin, a first-line drug for type 2 diabetes, reduces blood glucose by activating adenosine monophosphate protein kinase (AMPK) signalling system. However, the effect of Metformin on diabetic neuropathic pain is still unknown. In the present study, we showed that Metformin was capable of attenuating diabetes induced mechanical allodynia, and the analgesia effect could be blocked by Compound C (an AMPK inhibitor). Importantly, Metformin enhanced the phosphorylation level of AMPK in L4-6 DRGs of diabetic rats but not affect the expression of total AMPK. Intrathecal injection of AICAR (an AMPK agonist) could activate AMPK and alleviate the mechanical allodynia of diabetic rats. Additionally, phosphorylated AMPK and NF-κB was co-localized in small and medium neurons of L4-6 DRGs. Interestingly, the regulation of NF-κB in diabetic rats was obviously reduced when AMPK was activated by AICAR. Notably, Metformin could decrease NF-κB expression in L4-6 DRGs of diabetic rats, but the decrease was blocked by Compound C. In conclusion, Metformin alleviates diabetic mechanical allodynia via activation of AMPK signaling pathway in L4-6 DRGs of diabetic rats, which might be mediated by the downregulation of NF-κB, and this providing certain basis for Metformin to become a potential drug in the clinical treatment of diabetic neuropathic pain.



中文翻译:

二甲双胍通过AMPK/NF-κB信号通路减轻糖尿病大鼠背根神经节的糖尿病神经性疼痛

神经性疼痛是糖尿病的常见并发症,常规镇痛药难以缓解。二甲双胍是 2 型糖尿病的一线药物,通过激活单磷酸腺苷蛋白激酶 (AMPK) 信号系统来降低血糖。然而,二甲双胍对糖尿病神经性疼痛的影响仍不清楚。在本研究中,我们发现二甲双胍能够减轻糖尿病引起的机械性异常性疼痛,并且镇痛作用可以被化合物 C(一种 AMPK 抑制剂)阻断。重要的是,二甲双胍增强了糖尿病大鼠 L4-6 DRGs 中 AMPK 的磷酸化水平,但不影响总 AMPK 的表达。鞘内注射 AICAR(一种 AMPK 激动剂)可以激活 AMPK 并减轻糖尿病大鼠的机械异常性疼痛。此外,磷酸化的 AMPK 和 NF-κB 共定位于 L4-6 DRGs 的中小型神经元中。有趣的是,当 AMPK 被 AICAR 激活时,糖尿病大鼠对 NF-κB 的调节明显降低。值得注意的是,二甲双胍可降低糖尿病大鼠 L4-6 DRGs 中 NF-κB 的表达,但该降低被化合物 C 阻断。 总之,二甲双胍通过激活糖尿病大鼠 L4-6 DRGs 的 AMPK 信号通路减轻糖尿病机械性异常性疼痛,这可能是由NF-κB的下调介导的,这为二甲双胍成为临床治疗糖尿病神经性疼痛的潜在药物提供了一定的基础。

更新日期:2021-09-24
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