Topiramate Attenuates Cadmium-Induced Nephrotoxicity Through Modulation of Oxidative Stress, Autophagy, and Apoptosis in Rats.

Besides its traditional uses for epilepsy/migraine, topiramate has demonstrated remarkable antioxidant and anti-apoptotic features. In this study, we investigated the potential role of topiramate in mitigating cadmium-induced nephrotoxicity in rats, focusing on oxidative stress, apoptosis, and autophagy. Twenty-four male Wistar rats were randomly allocated into control, topiramate, cadmium, and cadmium + topiramate groups. Nephrotoxicity was induced by oral cadmium chloride (5 mg/kg/day) for 2 months, while topiramate (50 mg/kg/day) was co-administered orally. Renal injury, oxidative stress indices, autophagy-, and apoptosis-related proteins were examined using histopathology, ELISA, and immunohistochemistry. This study showed significant renal damage, manifested as multiple histological aberrations, elevated blood urea nitrogen and serum creatinine, along with elevated renal expression of kidney injury molecule-1 (KIM-1). Topiramate co-treatment reduced blood urea nitrogen and serum creatinine by 37.7% and 39%, respectively, and lowered KIM-1 by 36.9%, while lowering the endothelial/glomerular/tubular/interstitial (EGTI) histopathological damage score by 52.9%. Mechanistically, topiramate mitigated cadmium-induced nephrotoxicity by suppressing renal pro-oxidants and augmenting several antioxidant signals, including sirtuin 1 (SIRT1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and heme oxygenase 1 (HO-1) by 71.3%, 120.8%, and 78.7%, respectively. It also alleviated autophagy impairment by reducing sequestosome-1/protein 62 (SQSTM-1/p62) accumulation by 52.2% while activating AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) pathway. Additionally, topiramate curtailed apoptosis, as evidenced by increased B cell lymphoma 2 (Bcl-2) protein levels and lowered Bcl-2-associated x protein (Bax) expression and caspase-3 activity. Collectively, promoting SIRT1/Nrf2 antioxidant pathway, enhancing AMPK/mTOR-directed autophagy, and dampening renal apoptosis were involved in topiramate's protection against cadmium nephrotoxicity.