Chemobrain 是基于阿霉素 (DOX) 的化疗的一种具有挑战性的副作用，会损害癌症幸存者的认知能力。 DOX 通过氧化应激触发化学脑，导致炎症和细胞凋亡。 Empagliflozin (EMPA) 是一种钠葡萄糖协同转运蛋白 2 抑制剂，通过减少活性氧 (ROS) 和炎症表现出神经保护作用，但其针对 DOX 诱导的化学脑的保护机制尚不完全清楚。因此，本研究旨在研究 EMPA 对 DOX 诱导的大鼠趋化脑的神经保护作用，并揭示潜在的保护机制。将 50 只雄性 Wistar 大鼠分为对照组、EMPA、DOX（2mg/kg，IP，每周一次，持续 4 周）和两个治疗组（DOX EMPA 5 和 10mg/kg/天，PO，持续 4 周）。行为测试显示，与 DOX 相比，EMPA 治疗组的记忆力、运动表现得到改善，焦虑减少，且较高剂量的效果更佳。组织病理学分析显示，EMPA 治疗组的皮质和海马完整神经元增加，其中 CA3 增加 346.4%（p < 0.0001），齿状回增加 19.1%（p = 0.0006），皮质增加 362.6%（p < 0.0001）高剂量 EMPA 组。高剂量 EMPA 组的生化研究显示炎症和细胞凋亡标记物 (JNK/PARP-1/NLRP3/MuRF-1/FOXO-1) 显着减少，SIRT-1 蛋白表达增加 389.9% (p < 0.0001)，相对于 DOX 组，miRNA-34a 和 LncRNA HOTAIR 基因表达减少（分别为 50.4% 和 53.4%，p < 0.0001）。总之，EMPA 表现出优异的行为和组织病理学结果，特别是在较高剂量下，将其定位为一种有前途的针对 DOX 诱导的化学脑的神经保护候选药物，可能通过调节 SIRT-1、NF-κb、IL-1β 和氧化应激途径。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Chemobrain, a challenging side effect of Doxorubicin (DOX)-based chemotherapy, impairs cognitive abilities in cancer survivors. DOX triggers chemobrain via oxidative stress, leading to inflammation and apoptosis. Empagliflozin (EMPA), a sodium glucose co-transporter-2 inhibitor, demonstrated neuroprotective effects by reducing reactive oxygen species (ROS) and inflammation, but its protective mechanisms against DOX-induced chemobrain is not fully known. Thus, this study aimed to investigate EMPA's neuroprotective effects on DOX-induced chemobrain in rats and to uncover the underlying protective mechanisms. Fifty male Wistar rats were divided into control, EMPA, DOX (2mg/kg, IP, once/week for 4 weeks), and two treated groups (DOX+ EMPA 5 and 10mg/kg/day, PO, for 4 weeks). Behavioral tests showed improved memory, motor performance, and reduced anxiety in EMPA-treated groups compared to DOX, with superior results at the higher dose. Histopathological analysis revealed increased intact neurons in the cortex and hippocampus in EMPA-treated groups, with 346.4% increase in CA3 (p < 0.0001), 19.1% in dentate gyrus (p = 0.0006), and 362.6% in cortex (p < 0.0001) in the high-dose EMPA group. Biochemical investigations of the high-dose EMPA group revealed significant decreases in inflammatory and apoptotic markers (JNK/PARP-1/NLRP3/MuRF-1/FOXO-1), increased SIRT-1 protein expression by 389.9% (p < 0.0001), and reduced miRNA-34a and LncRNA HOTAIR gene expression (50.4% and 53.4% respectively, p < 0.0001) relative to DOX group. Conclusively, EMPA demonstrated superior behavioral and histopathological outcomes particularly at higher dose, positioning it as a promising neuroprotective candidate against DOX-induced chemobrain, possibly through modulating SIRT-1, NF-κb, IL-1β, and oxidative stress pathways.Copyright © 2024 Elsevier B.V. All rights reserved.