Combination of rosuvastatin and curcumin outperforms monotherapies in alleviating gentamicin-induced nephrotoxicity, audiotoxicity and vestibulotoxicity in a rat animal model.

The burden of nephrotoxicity and ototoxicity consequences caused by gentamicin warrants preventive therapeutic measures. Our aim was to evaluate combined and potentially synergistic effects of rosuvastatin and curcumin, both possessing anti-inflammatory and antioxidant properties, compared to their monotherapies in a gentamicin-induced model of nephrotoxicity and ototoxicity. In a randomized, controlled study, 36 male Wistar rats were allocated to six groups and treated for 5 days: negative control group received solvent, model group gentamicin (100 mg/kg, intraperitoneally), treatment groups gentamicin and via orogastric tube either standard-dose rosuvastatin (5 mg/day), reduced-dose rosuvastatin (1.25 mg/day), curcumin (100 mg/kg), or combination of reduced-dose rosuvastatin and curcumin. Human rosuvastatin doses were converted to rat doses using the conversion factor of 6.2. Functional outcomes evaluated by Preyer pinna reflex for hearing and a vestibular battery test were complemented by renal and cochlear histology, biochemical biomarkers of injury, inflammation, and oxidative stress. Gentamicin induced proximal tubular necrosis and cochlear and vestibular damage. Compared to monotherapies, combination therapy significantly preserved renal architecture, improved renal biomarkers, reduced early inflammatory biomarkers, preserved cochlear architecture and drove vestibular protection. It also alleviated gentamicin-induced cardiotoxicity. Rosuvastatin provided stronger auditory protection, with reduced-dose rosuvastatin superior to standard-dose in preserving vestibular function. Bliss independence modelling showed that combined therapy synergistically inhibited kidney injury and inflammation. In conclusion, the combination of reduced-dose rosuvastatin and curcumin outperforms both monotherapies in alleviating gentamicin-induced nephrotoxicity, audiotoxicity and vestibulotoxicity, whilst synergistically attenuating nephrotoxicity and early-phase inflammation in rats. These findings highlight promising preventive strategies against aminoglycoside nephrotoxicity and ototoxicity.