Vincamine Counteracts Gentamicin-Induced Parotid Gland Toxicity: Insights Into Antioxidant Defense, TRPC1/CHOP Modulation and Ferroptosis-Related Pathways

Background: Gentamicin (GET) is a widely used antibiotic, but its administration can cause parotid gland toxicity. Vincamine (VIN), a purified alkaloid with antioxidant and cytoprotective properties, may exert protective effects against gentamicin-induced toxicity. This study investigated the involvement of ferroptosis in GET-induced parotid gland toxicity and evaluated the protective effects of VIN and its potential underlying mechanisms. Methods: Adult male rats were divided into four groups: control, GET (100 mg/kg, i.p.), VIN (40 mg/kg, p.o.), and GET/VIN. Treatments were administered for 7 days. Parotid gland injury was evaluated by measuring serum lactate dehydrogenase (LDH) levels. Oxidative stress and cellular damage were assessed by measuring total antioxidant capacity (TAC), glutathione homeostasis (glutathione (GSH)/oxidized glutathione (GSSG)), and lipid peroxidation based on malondialdehyde (MDA) levels. Ferroptosis-related markers (glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), transferrin receptor 1 (TFR1), ferroportin 1 (FPN1), ferritin heavy chain 1 (FTH1) and Nrf2/HO-1 expression), were analyzed. Endoplasmic reticulum stress-related markers, including C/EBP homologous protein (CHOP), PERK, GRP78, and transient receptor potential canonical 1 (TRPC1), were also evaluated. Histopathological examinations were also performed. Results: GET significantly increased LDH levels and oxidative stress and induced parotid tissue damage. VIN treatment markedly reduced LDH levels, and attenuated oxidative stress. These protective effects were associated with modulation of Nrf2/HO-1 signaling and ferroptosis-related markers, including GPX4 and SLC7A11. VIN treatment was also associated with reduced markers of endoplasmic reticulum stress (CHOP, GRP78 and PERK) as well as restored TRPC1. Conclusions: VIN exerted protective effects against GET-induced parotid gland toxicity, accompanied by reduced oxidative stress and modulation of ferroptosis- and endoplasmic reticulum stress-related pathways. These findings suggest that VIN may have potential for further investigation as a protective agent against gentamicin-induced parotid gland injury.