Suppressing BRD4 exhibits protective effects against vincristine-induced peripheral neuropathy by alleviating inflammation and oxidative stress

Abstract

Vincristine (VCR) is a well-known anticancer drug, and frequently causes painful neuropathy and impairs the quality of life of patients. However, the molecular mechanisms revealing VCR-induced neuropathy are still unclear, and effectively therapeutic strategy is still necessary. Bromodomain-containing protein 4 (BRD4) has long been implicated in many different pathological processes, in particular, the development of oxidative stress and inflammation. In the present study, we showed that BRD4 played a mechanistic role in VCR-induced peripheral neuropathy. Using the in vivo transfection of BRD4 siRNA, we found that BRD4 suppression markedly alleviated VCR-induced neuropathic pain. Macrophage infiltration in sciatic nerve was effectively inhibited in VCR-challenged mice with BRD4 knockdown, as evidenced by the markedly reduced expression of F4/80. In the VCR-induced sciatic nerve tissues, we found that the mRNA and protein expression levels of C-X3-C motif chemokine receptor 1 (CX3CR1) and C-C chemokine receptor type 2 (CCR2) were greatly elevated, which were, however, mitigated by siBRD4 injection. In addition, oxidative stress induced by VCR was markedly restrained in sciatic nerve from mice with BRD4 knockdown, which was closely associated with the improved activation of nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling. The in vitro studies indicated that in H₂O₂-stimulated primary neurons, BRD4 silence markedly reduced reactive oxygen species (ROS) production and improved Nrf-2 activation, exhibiting anti-oxidant effects. Finally, BRD4 selective inhibitor JQ1 was subjected to mice challenged with VCR. The results confirmed that reducing BRD4 expression by JQ1 effectively ameliorated VCR-induced peripheral neuropathy also through repressing macrophage infiltration, inflammatory response and oxidative stress. Taken together, these findings demonstrated that BRD4 played a critical role in VCR-induced neuropathy, and developing novel and new therapies might be effective for the treatment of VCR-induced neuropathic pain.

Keywords: BRD4; Inflammation and oxidative stress; JQ1; Nrf-2; Vincristine.