Alsufyani Shuruq E, Eid Ahmed H, Althobaiti Musaad M, El-Sheikh Azza A K, Arafa El-Shaimaa A, Ashour Ahmed M, Arab Hany H
Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia.
Department of Pharmacology, Egyptian Drug Authority (EDA), formerly NODCAR, Giza, Egypt.
Biol Trace Elem Res. 2025 Jul 11. doi: 10.1007/s12011-025-04736-5.
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.
除了在癫痫/偏头痛方面的传统用途外，托吡酯还具有显著的抗氧化和抗凋亡特性。在本研究中，我们研究了托吡酯在减轻镉诱导的大鼠肾毒性中的潜在作用，重点关注氧化应激、细胞凋亡和自噬。将24只雄性Wistar大鼠随机分为对照组、托吡酯组、镉组和镉+托吡酯组。通过口服氯化镉（5毫克/千克/天）诱导肾毒性2个月，同时口服托吡酯（50毫克/千克/天）。使用组织病理学、酶联免疫吸附测定（ELISA）和免疫组织化学检测肾损伤、氧化应激指标、自噬和凋亡相关蛋白。本研究显示出显著的肾损伤，表现为多种组织学异常、血尿素氮和血清肌酐升高，以及肾损伤分子-1（KIM-1）的肾表达升高。联合使用托吡酯可使血尿素氮和血清肌酐分别降低37.7%和39%，使KIM-1降低36.9%，同时使内皮/肾小球/肾小管/间质（EGTI）组织病理学损伤评分降低52.9%。从机制上讲，托吡酯通过抑制肾促氧化剂并增强包括沉默调节蛋白1（SIRT1）、核因子（红系衍生2）样2（Nrf2）和血红素加氧酶1（HO-1）在内的多种抗氧化信号来减轻镉诱导的肾毒性，分别提高了71.3%、120.8%和78.7%。它还通过使聚集体蛋白1/蛋白质62（SQSTM-1/p62）积累减少52.2%，同时激活腺苷酸活化蛋白激酶（AMPK）/雷帕霉素靶蛋白（mTOR）途径来减轻自噬损伤。此外，托吡酯减少了细胞凋亡，这表现为B细胞淋巴瘤2（Bcl-2）蛋白水平升高以及Bcl-2相关X蛋白（Bax）表达降低和半胱天冬酶-3活性降低。总体而言，促进SIRT1/Nrf2抗氧化途径、增强AMPK/mTOR介导的自噬以及减轻肾细胞凋亡参与了托吡酯对镉肾毒性的保护作用。
