Docosahexaenoic acid improved vincristine-induced peripheral neuropathy in a rat model

Peripheral neuropathy is a common and debilitating complication of chemotherapy, characterized by nociceptive hypersensitivity with concurrent mitochondrial dysfunction, oxidative stress, and inflammation. Although nutraceutical supplement with Docosahexaenoic Acid (DHA) improves cancer treatment outcome and complications, molecular mechanisms responsible for beneficial effects are not well understood. Using a Sprague-Dawley rat model of vincristine-induced peripheral neuropathy, herein, we provide behavioral, histological, biochemical, and molecular evidence showing that DHA pretreatment alleviates chemotherapy-induced peripheral neuropathy. Nociceptive hypersensitivity and spinal cord dorsal horn neurodegeneration were accompanied by spinal cord dorsal horn nociceptive Interleukin-6 expression, NADPH oxidase 2 elevation, malondialdehyde production, superoxide dismutase activity inhibition, and glutathione reduction as well as circulating immune cell activation. In parallel, reduction of protein expression crucial to mitochondrial biogenesis, fission, and mitophagy as well as antioxidative defense and anti-inflammation was seen. DHA had alleviative effects on vincristine-induced changes. In assessing molecular targets, Peroxisome Proliferator-Activated Receptor γ (PPAR-γ) represented a surrogate candidate to coordinate action cascades in alleviating mitochondrial dysfunction, oxidative stress, and inflammation when activated by DHA. Although there remain limitations and further investigation is warranted, DHA supplementation is proposed as a protective strategy to alleviate chemotherapy-induced peripheral neuropathy. Our findings further imply that the mechanisms by which DHA is able to induce pain relief, directly or indirectly, could involve mitochondrial dysfunction, oxidative stress, and inflammation.