Treatment of Compound 968 and CU1015 Reduces Chemotherapy-Induced Peripheral Neuropathy in CD-1 Mice

Chemotherapy-induced peripheral neuropathy (CIPN) affects millions of patients, substantially impacting their quality of life. However, there are few effective treatments available for alleviating CIPN. Therefore, discovering new approaches to manage neuropathic pain is in high medical demand. Compound 968 (C968) and CU1015, both identified as glutaminase inhibitors with applications in cancer therapy, have shown promise in enhancing the anti-cancer activities of chemotherapy drugs in previous studies. However, their potential impact on CIPN has not been fully elucidated. This study aims to determine the effects of C968 and CU1015 on pain and opioid signaling in the CIPN mouse model. The CD-1 male and female mice received 4 doses of paclitaxel (intraperitoneal injection) to induce CIPN. Following CIPN development, mice were treated with C968 or CU1015 (intrathecal injection) 24 hours prior to morphine administration. To assess the impact of C968 or CU1015 on CIPN development, mice were treated with these inhibitors while concurrently receiving paclitaxel injections. The mechanical threshold was measured using the von Frey filaments. We found that spinal treatment with C968 or CU1015 enhanced the morphine analgesia in the CIPN induced by the injection of paclitaxel. Treatment with C968 or CU1015 also attenuated the development of CIPN in the male mice, but not in the female mice. The sex difference may be linked to the activation of ERK and Akt in the spinal cord. These findings underscore the promising role of C968 and CU1015 as therapeutic agents for neuropathic pain associated with chemotherapy.