Metformin Relieves Bortezomib-Induced Neuropathic Pain by Regulating AMPKa2-Mediated Autophagy in the Spinal Dorsal Horn

Neurochem Res. 2022 Mar 12. doi: 10.1007/s11064-022-03571-7. Online ahead of print.ABSTRACTChemotherapy-induced neuropathic pain is a major clinical problem with limited treatment options. Here, we show that metformin relieves bortezomib (BTZ)-evoked induction and maintenance of neuropathic pain by preventing the reduction in the expression of Beclin-1, an autophagy marker, in the spinal dorsal horn. Application of rapamycin or 3-methyladenine, autophagy inducer and inhibitor, respectively, affected the mechanical allodynia differently. Co-application of 3-methyladenine and metformin partially inhibited the effect of metformin in recovering Beclin-1 expression and in reducing the pain behavior in rats subjected to BTZ treatment. BTZ treatment also reduced the expression of AMPKa2 in the dorsal horn, which was recovered by metformin treatment. Overexpression of AMPKa2 attenuated the BTZ-evoked reduction in Beclin-1 expression and mechanical allodynia, whereas intrathecal injection of AMPKa2 siRNA decreased the Beclin-1 expression and induced mechanical allodynia in naive rats. Moreover, BTZ treatment increased the GATA3 expression in the dorsal horn, and GATA3 siRNA attenuated the AMPKa2 downregulation and mechanical allodynia induced by BTZ. Chromatin immunoprecipitation further showed that BTZ induced an increased recruitment of GATA3 to multiple sites in the AMPKa2 promoter region. Furthermore, decreased acetylation and increased methylation of histone H3 in the AMPKa2 prom...
Source: Neurochemical Research - Category: Neuroscience Authors: Source Type: research