Epigallocatechin-3-gallate attenuates colistin-induced neuro and nephrotoxicity by preserving mitochondrial function and reducing oxidative stress

Colistin, a last-resort antibiotic against multidrug-resistant Gram-negative infections, is limited by severe nephrotoxicity and neurotoxicity driven by oxidative stress and mitochondrial dysfunction. Effective neuroprotective strategies, particularly targeting the central nervous system, remain scarce. This study aimed to identify a natural compound capable of mitigating colistin-induced toxicity through an integrated in vitro and in vivo analysis. Five bioactive molecules with antioxidant and mitochondrial-stabilizing properties were screened in primary neuronal cultures exposed to colistin. Among them, epigallocatechin-3-gallate (EGCG) emerged as the most effective candidate. Its protective actions were then evaluated in a mouse model of colistin toxicity using molecular, histopathological, and behavioral assessment. EGCG pretreatment prevented colistin-induced weight loss, renal tubular apoptosis, and neuromotor impairment while preserving muscle strength. In the central nervous system, EGCG maintained dendritic spine density, reduced caspase-3 activity, and attenuated astrogliosis. Mechanistically, its benefits were associated with reduced reactive oxygen species levels and preserved mitochondrial membrane potential in vitro. Behavioral analysis further supported these findings, revealing improvements in recognition memory and reductions in anxiety- and depressive-like behaviors. Overall, this study provides comprehensive evidence that EGCG confers broad neuro- and nephroprotective effects against colistin toxicity, highlighting its potential as a safe adjuvant to enhance the therapeutic window of polymyxins.