Metformin attenuates diabetic neuropathic pain via AMPK/NF-κB signaling pathway in dorsal root ganglion of diabetic rats
Metformin attenuates diabetic neuropathic pain via AMPK/NF-κB signaling pathway in dorsal root ganglion of diabetic rats
复制标题
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
DOI：
10.1016/j.brainres.2021.147663
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发表时间：
2021-09-24
期刊：
影响因子：
2.9
通讯作者：
Zhang, Ping-An
中科院分区：
文献类型：
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作者：
Cao, Xiao-Jun;Wu, Rui;Zhang, Ping-An
神经病理性疼痛是糖尿病常见的并发症，传统的镇痛药物难以缓解。二甲双胍是治疗2型糖尿病的一线药物，通过激活腺苷一磷酸蛋白激酶（AMPK）信号系统降低血糖。然而，二甲双胍对糖尿病神经病理性疼痛的影响仍然是未知的。在本研究中，我们发现Metalloy能够减轻糖尿病引起的机械异常性疼痛，并且镇痛作用可以被化合物C（AMPK抑制剂）阻断。重要的是，二甲双胍可提高糖尿病大鼠L4-6 DRG中AMPK的磷酸化水平，但不影响总AMPK的表达。鞘内注射AMPK激动剂AICAR可激活AMPK，减轻糖尿病大鼠的机械性痛觉超敏。此外，磷酸化AMPK和NF-κ B B共定位于L4-6背根神经节的小型和中型神经元。有趣的是，AICAR激活AMPK后，糖尿病大鼠NF-κ B的调节明显减弱。值得注意的是，二甲双胍可以降低糖尿病大鼠L4-6 DRG中的NF-κ B表达，但该降低被化合物C阻断。综上所述，二甲双胍通过激活糖尿病大鼠L4-6背根神经节AMPK信号通路，下调NF-κ B B的表达，减轻糖尿病机械性痛觉超敏，为二甲双胍成为糖尿病神经病理性疼痛的潜在临床治疗药物提供了一定的依据。
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-kappa B was co-localized in small and medium neurons of L4-6 DRGs. Interestingly, the regulation of NF-kappa B in diabetic rats was obviously reduced when AMPK was activated by AICAR. Notably, Metformin could decrease NF-kappa B 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-kappa B, and this providing certain basis for Metformin to become a potential drug in the clinical treatment of diabetic neuropathic pain.