Abstract
Background:
Gentamicin is a widely used aminoglycoside antibiotic; however, its clinical application is limited by dose-dependent hepatotoxicity and nephrotoxicity, mainly mediated through oxidative stress, inflammation, and apoptosis. Plant-derived natural antioxidants may provide protection against drug-induced organ injury.

Aim:
This study aimed to evaluate and compare the protective effects of chia seed extract (CSE) and red grape seed extract (RGSE) against gentamicin-induced hepatorenal toxicity in rats. Previous studies have largely investigated these extracts separately, with limited direct comparative evidence under the same experimental conditions. In addition, the roles of oxidative stress, inflammatory mediators, and apoptotic pathways have not been fully clarified using integrated biochemical, histopathological, and immunohistochemical approaches. Therefore, this study was designed to compare the prophylactic efficacy of CSE and RGSE and to explore the mechanisms underlying their protective effects.

Methods:
Sixty adult male Sprague–Dawley rats were randomly assigned to 10 experimental groups (n = 6/group). Hepatorenal toxicity was induced by gentamicin administration (80 mg/kg body weight). Rats received CSE (10 and 20 mg/kg) or RGSE (200 and 400 mg/kg), either alone or in combination with gentamicin, for 21 days. Liver and kidney function indices, oxidative stress biomarkers (Malondialdehyde (MDA) , Glutathione, glutathione S-transferase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and vitamins C and E), histopathological changes, and immunohistochemical expression of TNF-α and Caspase-3 were assessed.

Results:
Gentamicin significantly increased oxidative stress, elevated serum liver enzymes (alanine aminotransferase and aspartate aminotransferase), and induced marked hepatic and renal histopathological alterations (p < 0.05). Treatment with both extracts significantly reduced MDA levels, restored antioxidant enzyme activities, improved biochemical indices, and attenuated tissue injury. RGSE exhibited greater protective efficacy than CSE, with more pronounced suppression of TNF-α and Caspase-3 expression.

Conclusion:
Both chia seed and RGSEs exerted significant protective effects against gentamicin-induced hepatorenal toxicity through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms, with RGSE showing comparatively greater efficacy. Further translational studies are warranted to confirm their clinical applicability.

Key words: Caspase-3; Chia seed; Grape seed; Oxidative stress; TNF-α.