The effects of chemotherapy on brain regions: implications for chemobrain revealed through metabolomic profiling

Chemobrain (CMB) is a common complication that affects the majority of cancer patients and can persist for years following chemotherapy. Common symptoms are deficits in memory, attention, and affective regulation, yet they are mainly diagnosed through patient-reported symptoms. Additionally, the molecular mechanisms underlying CMB remain poorly understood, limiting the development of effective neuroprotective strategies for cancer patients. Using a rat model of CMB, this study investigates the molecular impact of doxorubicin (DOX) and temozolomide (TMZ), administered individually and in combination in comparison with a control group (n = 10/group). Untargeted metabolomic profiling was performed on the cortex, cerebellum, and hippocampus tissues after performing the neurobehavioural tests. Behavioural assessments revealed impaired spatial learning and memory, particularly in the combination-treated group, together with alterations in anxiety-related behaviour. The metabolites were extracted from their respective tissues using a two-in-one extraction protocol and were analysed by TIMS-QTOF-MS/MS. DOX treatment was associated with relatively modest region-specific metabolic alterations, with patterns consistent with possible oxidative stress-related and membrane-associated responses. TMZ treatment was associated with metabolic changes involving nucleotide metabolism and energy-related pathways, particularly in the hippocampus. The combination treatment showed a distinct metabolic profile with partial qualitative overlap with TMZ-associated alterations. Overall, these findings suggest that chemotherapy exposure is associated with region-specific metabolic alterations that co-occur with behavioural changes relevant to a CMB-like phenotype. The present results should be interpreted as exploratory and hypothesis-generating, pending targeted metabolite validation and orthogonal mechanistic confirmation. Ultimately, understanding these responses can provide critical insights into CMB pathophysiology and may lay the groundwork for the development of targeted diagnostic, monitoring, and neuroprotective strategies.