Clinically relevant dose of doxorubicin induces persistent alterations in the hippocampal formation of CD-1 Mice

Doxorubicin (DOX), an anthracycline chemotherapeutic agent, is associated with multiple adverse effects, including persistent cognitive impairment, commonly referred to as "chemobrain." This study aimed to evaluate the long-term neurotoxic effects of a clinically relevant cumulative dose of DOX in a rodent model. Three-month-old male CD-1 mice received DOX twice a week for three weeks, reaching a cumulative dose of 9.0 mg/kg. Brain tissue was analysed five months after the final administration to assess enduring neurotoxic effects. Coronal sections of the left hemisphere were evaluated for biomarkers related to apoptosis, inflammation, glial function, and neuronal integrity in the prefrontal cortex (PFC) and hippocampal formation (HF). Additionally, a significant reduction in Iba1-immunoreactive microglia and nuclei was found in the HF. Additionally, p53 levels remained elevated, while procaspase-3 levels decreased, suggesting persistent changes in apoptotic pathways. A significant reduction in brain-derived neurotrophic factor (BDNF) levels was observed in the dentate gyrus (DG), indicating impaired neurogenesis. In contrast, no substantial changes were detected in the PFC, highlighting the selective vulnerability of the HF to DOX-induced neurotoxicity. These findings underscore the enduring impact of DOX on HF and suggest potential mechanisms underlying long-term cognitive deficits observed in chemotherapy-treated patients.