Mitoquinone alleviates vincristine-induced neuropathic pain through inhibiting oxidative stress and apoptosis via the improvement of mitochondrial dysfunction

Abstract

Chemotherapy drugs such as vincristine (Vin) could cause neuropathic pain. However, it is still lack of ideal therapeutic strategy to treat it. Mitochondrial dysfunction has been involved in the pathogenesis of neuropathic pain. The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is able to modify mitochondrial signaling, showing beneficial effects on various diseases. In the study, we investigated whether MitoQ could regulate Vin-induced neuropathic pain, and the underlying molecular mechanisms. The results showed that MitoQ significantly improved Vin-induced pain hypersensitivity and glial activation in mice. In addition, Vin resulted in severe oxidative stress in spinal cord tissues of mice, which were inhibited by MitoQ treatment through improving Nrf2 (NF-E2-related factor 2) expression in nuclear. Also, MitoQ treatment dose-dependently reduced the expression of pro-inflammatory cytokines, indicating its anti-inflammatory effects. Importantly, Vin stimulation contributed to mitochondrial fission, as evidenced by the increased expression of phosphorylated Drp1 (dynamin related protein 1) and Fis (mitochondrial fission protein 1), whereas mitochondrial fussion was inhibited. However, these effects were notably abrogated by MitoQ, subsequently improving mitochondrial dysfunction. Moreover, neuron death evoked by Vin was significantly rescued by MitoQ treatment. We also observed significantly reduced expression of cleaved Caspase-3 and Bax expression in spinal cord of MitoQ-treated mice with Vin stimulation. In contrast, anti-apoptotic factor Bcl-2 protein levels decreased by Vin were restored by MitoQ. The process of Cyto-c release from mitochondria triggered by Vin was effectively inhibited in mice treated with MitoQ. These in vivo results were further verified in the primary neurons using the in vitro and ex vivo experiments. Furthermore, MitoQ treatment alleviated axonal degeneration and mitochondria dysfunction induced by Vin. Thus, mitoquinone could alleviate vincristine-induced neuropathic pain by inhibiting oxidative stress and apoptosis via the improvement of mitochondrial dysfunction.