Alattar Abdullah, Alshaman Reem, Althobaiti Yusuf S, Soliman Ghareb M, Ali Howaida S, Khubrni Waleed Salman, Koh Phil Ok, Rehman Najeeb Ur, Shah Fawad Ali
Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk 47713, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 21944, Taif 21944, Saudi Arabia.
Pharmaceuticals (Basel). 2023 Aug 21;16(8):1182. doi: 10.3390/ph16081182.
Stroke ranks as the world's second most prevalent cause of mortality, and it represents a major public health concern with profound economic and social implications. In the present study, we elucidated the neuroprotective role of quercetin on NLRP3-associated pyroptosis, Nrf2-coupled anti-inflammatory, and mTOR-dependent downstream pathways. Male Sprague Dawley rats were subjected to 72 h of transient middle cerebral artery ischemia, followed by the administration of 10 mg/kg of quercetin. Our findings demonstrated that MCAO induced elevated ROS which were coupled to inflammasome-mediated pyroptosis and altered mTOR-related signaling proteins. We performed ELISA, immunohistochemistry, and Western blotting to unveil the underlying role of the Nrf2/HO-1 and PDK/AKT/mTOR pathways in the ischemic cortex and striatum. Our results showed that quercetin post-treatment activated the Nrf2/HO-1 cascade, reversed pyroptosis, and modulated the autophagy-related pathway PDK/AKT/mTOR/P70S6/P6/eIF4E/4EBP1. Further, quercetin enhances the sequestering effect of 14-3-3 and reversed the decrease in interaction between p-Bad and 14-3-3 and p-FKHR and 14-3-3. Our findings showed that quercetin exerts its protective benefits and rescues neuronal damage by several mechanisms, and it might be a viable neuroprotective drug for ischemic stroke therapy.
中风是全球第二大常见死因，是一个重大的公共卫生问题，具有深远的经济和社会影响。在本研究中，我们阐明了槲皮素对NLRP3相关细胞焦亡、Nrf2偶联的抗炎以及mTOR依赖的下游通路的神经保护作用。对雄性Sprague Dawley大鼠进行72小时的短暂大脑中动脉缺血，随后给予10mg/kg的槲皮素。我们的研究结果表明，大脑中动脉闭塞（MCAO）诱导活性氧升高，这与炎性小体介导的细胞焦亡以及mTOR相关信号蛋白改变有关。我们进行了酶联免疫吸附测定（ELISA）、免疫组织化学和蛋白质免疫印迹法，以揭示Nrf2/HO-1和PDK/AKT/mTOR通路在缺血皮层和纹状体中的潜在作用。我们的结果表明，槲皮素治疗后激活了Nrf2/HO-1级联反应，逆转了细胞焦亡，并调节了自噬相关通路PDK/AKT/mTOR/P70S6/P6/eIF4E/4EBP1。此外，槲皮素增强了14-3-3的螯合作用，并逆转了p-Bad与14-3-3以及p-FKHR与14-3-3之间相互作用的减少。我们的研究结果表明，槲皮素通过多种机制发挥其保护作用并挽救神经元损伤，它可能是一种用于缺血性中风治疗的可行神经保护药物。
