ABSTRACT Letrozole, a widely used aromatase inhibitor for hormone receptor–positive breast cancer, has been suggested to be associated with potential neurotoxic effects; however, the underlying mechanisms remain unclear. This study aimed to investigate the neurotoxic effects of letrozole and evaluate the neuroprotective potential of hesperidin, a natural flavonoid with antioxidant and anti‐inflammatory properties. Adult female rats received letrozole alone or in combination with hesperidin for 4 weeks. Biochemical analyses showed that letrozole significantly increased total oxidant status (TOS) and decreased total antioxidant status (TAS), indicating oxidative stress. Gene expression results revealed upregulation of pro‐apoptotic Bax and downregulation of anti‐apoptotic Bcl 2 in letrozole‐treated rats, reflecting apoptotic activation. Additionally, inflammatory cytokine measurements demonstrated elevated pro‐inflammatory markers (IL‐1, IL‐6, TNF‐α) and reduced anti‐inflammatory IL‐10 following letrozole administration. Histopathological examination revealed cortical microhemorrhages, edema, and hyperemia. Importantly, co‐treatment with hesperidin attenuated oxidative imbalance, normalized apoptotic gene expression, modulated inflammatory cytokine levels towards an anti‐inflammatory profile, and ameliorated histological damage. These findings indicate that hesperidin confers neuroprotection by restoring redox balance, regulating apoptosis, and suppressing inflammation in letrozole‐induced neurotoxicity. Further studies are warranted to elucidate the precise molecular mechanisms and potential therapeutic applications of hesperidin in letrozole‐induced neurotoxicity.
Ayhan et al. (2026) studied this question.