ubiquinone and Neuralgia

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.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Apoptosis; Male; Mice; Mice, Inbred ICR; Mitochondria; Mitochondrial Dynamics; Neuralgia; Organophosphorus Compounds; Oxidative Stress; Ubiquinone; Vincristine

Diabetic neuropathic pain is reduced with tight glycemic control. However, strict control increases the risk of hypoglycemic episodes, which are themselves linked to painful neuropathy. This study explored the effects of hypoglycemia-related painful neuropathy. Pretreatment with coenzyme Q10 (CoQ10) was performed to explore the preventive effect of CoQ10 on hypoglycemia-related acute neuropathic pain. Two strains of mice were used and 1 unit/kg of insulin was given to induce hypoglycemia. Mechanical sensitivity of hindpaw withdrawal thresholds was measured using von Frey filaments. Blood glucose levels were clamped at normal levels by joint insulin and glucose injection to test whether insulin itself induced hypersensitivity. Results suggest that the increased mechanical sensitivity after insulin injection is related to decreased blood glucose levels. When blood glucose levels remained at a normal level by the linked administration of insulin and glucose, mice demonstrated no significant change in mechanical sensitivity. Pretreatment with CoQ10 prevented neuropathic pain and the expression of the stress factor c-Fos. These results support the concept that pain in the diabetic scenario can be the result of hypoglycemia and not insulin itself. Additionally, pretreatment with CoQ10 may be a potent preventive method for the development of neuropathic pain.

Topics: Acute Disease; Analgesics; Animals; Biomarkers; Blood Glucose; Disease Models, Animal; Hyperalgesia; Hypoglycemia; Insulin; Mice, Inbred C57BL; Mice, Inbred CBA; Neuralgia; Pain Threshold; Proto-Oncogene Proteins c-fos; Spinal Cord; Time Factors; Ubiquinone

Neuropathic pain is a common side-effect of chemotherapy. Although precise mechanisms are unclear, oxidative stress and mitochondrial damage are involved. We investigated whether the mitochondria targeted antioxidant, MitoVitE, provided better protection against paclitaxel-induced mitochondrial damage in rat dorsal root ganglion (DRG) cells, than a non-targeted form of vitamin E, Trolox. We also determined whether MitoVitE, compared with duloxetine, could limit paclitaxel-induced mechanical hypersensitivity in rats.. Mitochondrial function was measured in DRG cells exposed to paclitaxel with and without MitoVitE or Trolox. The effect of MitoVitE or Trolox on paclitaxel-induced cell killing in cancer cell lines was also determined. Rats received a cumulative dose of 8 mg kg. Paclitaxel caused loss of membrane potential in DRG cells. At 100 µM paclitaxel median [range] change was 61[44-78]%, P < 0.0001, which was ameliorated by MitoVitE (86[62-104]%) but not Trolox (46[46-57]%). Similarly, loss of metabolic activity and glutathione induced by paclitaxel (both P < 0.0001) were reduced by MitoVitE but not Trolox. Cytotoxicity of paclitaxel was not affected by co-exposure of ovarian cancer cells to either MitoVitE or Trolox, but was slightly reduced against breast cancer cells, in the presence of Trolox. Mean (SD) areas under the curve of withdrawal thresholds at 6 h after injection in rats given paclitaxel + control, or + MitoVitE (P < 0.0001) or + duloxetine (P < 0.0001) were 110 (5), 145 (10) and 156 (13) respectively.. Paclitaxel affected mitochondrial function and glutathione in DRG cells, which was abrogated by MitoVitE but not Trolox, without decreasing cancer cell cytotoxicity. In rats, paclitaxel-induced mechanical hypersensitivity was ameliorated by MitoVitE treatment to an extent similar to duloxetine. These data confirm mitochondria as a mechanistic target for paclitaxel-induced damage and suggest mitochondria targeted antioxidants as future therapeutic strategies.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Disease Models, Animal; Hyperalgesia; In Vitro Techniques; Male; Mitochondria; Neuralgia; Organophosphorus Compounds; Oxidative Stress; Paclitaxel; Rats; Rats, Sprague-Dawley; Ubiquinone