Evaluation of the Therapeutic Potential of Amantadine in a Vincristine-Induced Peripheral Neuropathy Model in Rats

Simple Summary Vincristine-induced peripheral neuropathy is a debilitating side effect and a limiting factor in the continuance of treatment of cancer patients. Thus, therapeutic strategies are necessary to enable the maintenance of oncological treatment and minimize undesired conditions caused by the treatment. Current protocols for the management of neuropathic pain remain unsatisfactory due to the complexity and severity of clinical signs, as well as the lack of significant improvement with pharmacological treatment. Amantadine shows therapeutic potential by acting on NMDA receptors. Immunohistochemistry, quantitative PCR and analysis of enzymatic activity were performed to demonstrate the therapeutic activity of amantadine in the spinal cord of rats with induced neuropathic pain. The authors herein demonstrated positive effects on the regulation of neuroinflammation, oxidative stress, reticulum endoplasmic stress and apoptosis with the highest doses examined (25 mg/kg and 50 mg/kg). We hope that our research will contribute to studies of amantadine as an option in a pharmacotherapeutic protocol for peripheral neuropathy.Abstract This study aimed to evaluate the therapeutic potential of amantadine in a vincristine-induced peripheral neuropathy model in rats. Forty-eight male Wistar rats were used. The treated groups received oral amantadine at doses of 2, 5, 12, 25 and 50 mg/kg, with daily applications for 14 days. The mechanical paw withdrawal threshold was measured using a digital analgesimeter. Immunohistochemical analysis of IL-6, TNF alpha, MIP1 alpha, IL-10, CX3CR1, CXCR4, SOD, CAT and GPx, and enzymatic activity analysis of CAT, SOD and GPx were performed, in addition to quantitative PCR of Grp78, Chop, Ho1, Perk, Bax, Bcl-xL, Casp 3, Casp 9, IL-6, IL-10, IL-18 and IL-1 beta. The results showed an increase in nociceptive thresholds in animals that received 25 mg/kg and 50 mg/kg amantadine. Immunohistochemistry showed a decrease in the immunostaining of IL-6, TNF alpha, MIP1 alpha and CX3CR1, and an increase in IL-10. CAT and SOD showed an increase in both immunochemistry and enzymatic analysis. qPCR revealed a reduced expression of genes related to endoplasmic reticulum stress and regulation in the expression of immunological and apoptotic markers. Amantadine demonstrated antinociceptive, anti-inflammatory and antioxidant effects in the vincristine-induced peripheral neuropathy model in rats, suggesting that amantadine may be considered an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.