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Chemotherapy-Induced Brain Damage: Mechanisms and Insights from Rodent Models
Milica Veljković1, Tanja Džopalić2, Pavle Ranđelović1
1Department of Physiology, Medical Faculty, University of Niš, Zoran Đinđić Boulevard 81, 18 000 Niš, Serbia.
Background/Objectives:
Chemotherapy-induced cognitive impairment, colloquially known as chemobrain, affects a substantial proportion of cancer patients. Preclinical rodent models help clarify underlying drug-specific neurotoxic effects, as well as histological, biochemical, molecular, and behavioral mechanisms.
Methods:
We conducted a narrative review of animal studies examining cognitive dysfunction following treatment with commonly used chemotherapeutic agents, including doxorubicin, cisplatin, cyclophosphamide, methotrexate, 5-fluorouracil, paclitaxel, and docetaxel. The review focused on behavioral and cognitive outcomes, and experimental parameters such as rodent models and dosing regimens.
Results:
Across studies, chemotherapeutic exposure has had a consistent negative effect on short-term and working memory, learning and other cognitive domains, with impairments being often mild and detectable even at doses not causing apparent systemic toxicity. Histological analyses revealed reduced neurogenesis, dendritic and myelin alterations, and glial activation, mainly in the hippocampus and prefrontal cortex. Biochemical and molecular changes included oxidative stress, pro-apoptotic signaling, inflammatory cytokine dysregulation, decreased neurotrophic support, and altered neurotransmitter dynamics. Age and sex influenced susceptibility, with juvenile or aged animals and females-particularly older females modeling breast cancer patients-showing greater deficits. Cumulative or repeated dosing exacerbated neurotoxicity, while single administrations produced milder, sometimes transient, impairments.
Conclusions:
Preclinical models provide compelling evidence that chemotherapeutic agents impair cognitive function via convergent mechanisms involving inflammation, oxidative stress, and synaptic dysregulation. These findings highlight the importance of considering age, sex, and treatment schedule in designing neuroprotective strategies and underscore the translational relevance of rodent models in understanding chemobrain.
