THYMOQUINONE AS A POSSIBLE NEUROPROTECTIVE AGENT AGAINST PACLITAXEL-INDUCED PERIPHERAL NEUROTOXICITY

Background: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and serious side effect associated with various chemotherapy agents, including paclitaxel (PTX). Unfortunately, current therapeutic approaches have shown limited efficacy in either preventing or mitigating neuropathic debilitating symptoms. Thymoquinone (TQ), the primary bioactive compound of Nigella sativa seeds, has exhibited notable potential in mitigating CIPN, particularly in acute preclinical models. However, its effectiveness in addressing chronic CIPN remains unestablished. To fill this research void, our study aimed to investigate the neuroprotective effect of TQ in preventing peripheral neurotoxicity induced by chronic PTX treatment in rats and to exclude its interference with the anticancer efficacy of PTX in vitro. Methods: In the vivo part, rats were administrated with PTX (10 mg/kg, i.v) once a week for 4 weeks to induce peripheral neuropathy. Concurrently, separate groups received either the vehicle or PTX combined with TQ, administered orally at doses of 5 mg/kg/day or 10 mg/kg/day for 4 weeks. In the in vitro part, MCF-7 breast cancer cells were treated with PTX 25 nM alone or plus TQ 25μM for 24, and 48 hours for mortality assessments (MTT test). Results: We observed that at mid-treatment and at the end of treatment, TQ effectively prevented the mechanical allodynia observed in PTX-treated rats. Furthermore, the quantitative analysis of intraepidermal nerve fibers revealed a significant reduction in the density of small unmyelinated fibers in the PTX group which was prevented at mid-treatment by PTX+TQ10. In addition, MTT assays revealed that TQ did not compromise PTX anticancer activity in MCF-7 breast cancer cells. Conclusions: Our preliminary data suggests a potential value of TQ in preventing PTX neurotoxic chronic effects, without interfering with its antineoplastic properties.