Evodiamine ameliorates paclitaxel-induced neuropathic pain by inhibiting inflammation and maintaining mitochondrial anti-oxidant functions

Chemotherapy-induced neuropathic pain (CINP) is a common and debilitating side effect of cancer treatment. Evodiamine, a major effective compound isolated from Evodia rutaecarpa, has been associated with anti-inflammatory and anti-nociceptive effects, an important therapeutic strategy for the treatment of neuropathic pain. However, the effects of evodiamine on CINP remain unknown. Thus, this study aims to investigate the pharmacological potential of evodiamine in attenuating paclitaxel-induced peripheral neuropathy. The results showed that evodiamine enhanced but not reduced the sensitivity of cancer cells to paclitaxel treatment. In a rat model of paclitaxel-induced peripheral neuropathy, evodiamine significantly ameliorated the development of mechanical and thermal hypersensitivity. Moreover, paclitaxel-induced the loss of intraepidermal nerve fibers was markedly inhibited by evodiamine administration. This inhibitory effect was accompanied with the decrease in inflammatory and chemoattractant cytokines level in dorsal root ganglia (DRG), such as interleukin (IL)-1, IL-6, tumor necrosis factor- and monocyte chemoattractant protein-1. In addition, evodiamine administration limited paclitaxel-induced elevation of oxidative stress in DRG tissues. The mitochondrial dysfunction evoked by paclitaxel was also remarkably improved in evodiamine-treated rats, evidenced by restoration of peroxisome proliferator-activated receptor gamma coactivator 1- (PGC-1), uncoupling protein 2 (UCP2), and superoxide dismutase 2 (SOD2) expression. In in vitro studies, we found that evodiamine prevented paclitaxel-induced the loss of mitochondrial membrane potential and PGC-1, UCP2 and SOD2 expression in DRG cells. In conclusion, our study demonstrates that evodiamine ameliorates paclitaxel-induced neuropathic pain by inhibiting inflammatory response and maintaining mitochondrial anti-oxidant functions, indicating that evodiamine may be a promising therapeutic agent for CINP treatment.