Protective Effects of Hesperidin on Letrozole‐Induced Neurotoxicity: Involvement of Oxidative Stress, Apoptotic Signaling, and Inflammation

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 Bcl2 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.