Notch activation enhances microglial CX3CR1/P38 MAPK pathway in rats model of vincristine-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) has a adverse impact to the living quality of cancer patients. This side effect of CIPN limit the dose of drug used in many chemotherapies, such as vincristine (VCR). The activation of microglia in the spinal dorsal horn is involved in the occurrence and development of neuropathic pain induced by VCR. Recent study has demonstrated that hypoxia induced microglia activation depends on Notch signaling, and it is involved in the release of many inflammatory related factors in microglia. In this work, we aimed to study that the role of Notch signaling pathway in microglia activation on a VCR-induced neuropathy rat model. Our results showed that the mechanical, thermal and cold pain threshold of rats was decreased by treatment of VCR, but N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase inhibitor, relieved the hyperalgesia. Molecular analysis showed that activation of Notch signaling pathway increased after nerve injury and that DAPT could significantly inhibit the upregulation of Notch signaling pathway, the activation of microglia, and the release of pro-inflammatory cytokines in the spinal. Taking together, Notch signaling pathway could be a potential therapeutic target to alleviate neuropathic pain.