Effect of Doxorubicin on Spatial Memory and Microscopic Morphology of Prefrontal Cortex and Hippocampus in Rats

Despite the clear successes of chemotherapy in oncology, a significant rise is observed in cognitive impairment during pharmacotherapy and recovery — a phenomenon known as chemobrain. Experimental study of mechanisms underlying chemobrain induction and its modeling provide a critical foundation for developing pharmacological strategies for prevention and correction. The study aimed to evaluate the dosedependent effects of doxorubicin administration on long-term spatial memory and the microscopic morphology of the prefrontal cortex and hippocampus in rats. Doxorubicin was administered intraperitoneally to outbred male white rats (n=40) at doses of 2, 3, and 5 mg/kg on days 1, 7, 14, and 21. Control animals received isotonic saline. Memory function was assessed using the Y-maze test on days 24 and 25, followed by a morphological examination of brain structures on day 32. Rats treated with doxorubicin exhibited a dose-dependent decrease in the time spent in the novel arm of the Y-maze, indicating impaired spatial memory. Microscopic examination revealed disrupted cerebral microcirculation in the prefrontal cortex, as well as in the hippocampal CA1 and CA3 regions (at the maximum dose of 5 mg/kg). These findings suggest that for modeling chemobrain, a doxorubicin dose of 2 mg/kg is optimal, as it induces cognitive impairment with minimal toxicity. Thus, we have experimentally justified the selection of the doxorubicin dose and the behavioral test for assessing spatial memory impairment preferred in chemobrain modeling, facilitating the search for and preclinical study of pharmacological strategies to prevent and correct chemotherapy side effects.

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