Trimetazidine protects against doxorubicin-induced chemobrain in rats: Insights into energy imbalance and neuroinflammation.

Chemotherapy-induced cognitive impairment is the second major complication associated with doxorubicin (DOX) administration after cardiomyopathy. Trimetazidine (TMZ) is a metabolic anti-anginal agent that exhibits anti-inflammatory, antioxidant and anti-apoptotic properties. The current study aims to assess the potential neuroprotective effect of TMZ against DOX-mediated cognitive impairment. Male Sprague Dawley rats were treated with DOX (2 mg/kg/week i.p.) for 5 weeks to induce chemobrain. TMZ was co-administered at either 30 or 60 mg/kg, p.o., 5 days a week for 7 weeks. Treatment with DOX induced cognitive deficits as evidenced by both behavioral tests and histological assessment which revealed moderate-to-severe neurodegeneration in the hippocampal and prefrontal cortex brain areas. DOX-treatment induced oxidative imbalance (↓GSH, ↑MDA), neuroinflammation (↑NF-kB, ↑TNF-α) and programmed cell death (↑cleaved-caspase-3). Moreover, DOX also induced perturbations in cellular bioenergetics (↓pAMPK, ↓PGC-1α, ↓NADP/NADPH, ↓ATP). Co-treatment with TMZ significantly mitigated DOX-induced alterations in behavioral, histological, and biochemical markers at both tested doses. Notably, the 60 mg/kg dose of TMZ demonstrated superior efficacy. These findings provide a strong rationale for further clinical evaluation of TMZ-DOX combination regimens as a potential strategy to prevent DOX-associated cognitive impairment.