Pharmacology Research Laboratory, Pharmacology Division, UGC Centre of Advanced Studies, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
Neurochem Res. 2023 Aug;48(8):2476-2489. doi: 10.1007/s11064-023-03914-y. Epub 2023 Apr 5.
Chemotherapy-induced cognitive impairment (CICI) is a common complication associated with the use of chemotherapeutics. Doxorubicin (DOX) is a reactive oxygen species (ROS) producing anticancer agent capable of causing potential neurotoxic effects via cytokine-induced oxidative and nitrosative damage to brain tissues. On the other hand, alpha-lipoic acid (ALA), a nutritional supplement, is reputable for its excellent antioxidant, anti-inflammatory, and anti-apoptotic activities. Consequently, the objective of the current investigation was to examine any potential neuroprotective and memory-improving benefits of ALA against DOX-induced behavioral and neurological anomalies. DOX (2 mg/kg/week, i.p.) was administrated for 4 weeks to Sprague-Dawley rats. ALA (50, 100, and 200 mg/kg) was administered for 4 weeks. The Morris water maze (MWM) and novel objective recognition task (NORT) tests were used to assess memory function. Biochemical assays with UV-visible spectrophotometry were used to analyze oxidative stress markers [malondialdehyde (MDA), protein carbonylation (PCO)], endogenous antioxidants [reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)] and acetylcholinesterase (AChE) activity in hippocampal tissue. Inflammatory markers [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and nuclear factor kappa B (NF-κB)], nuclear factor erythroid 2-related factor-2 (NRF-2) and hemeoxygenase-1 (HO-1) levels were estimated using enzyme-linked immunosorbent assay (ELISA). In addition, reactive oxygen species (ROS) levels were measured in hippocampus tissue using 2-7-dichlorofluorescein-diacetate (DCFH-DA) assay with fluorimetry. ALA treatment significantly protected against DOX-induced memory impairment. Furthermore, ALA restored hippocampal antioxidants, halted DOX-induced oxidative and inflammatory insults via upregulation of NRF-2/HO-1 levels, and alleviated the increase in NF-κB expression. These results indicate that ALA offers neuroprotection against DOX-induced cognitive impairment, which could be attributed to its antioxidant potential via the NRF-2/HO-1 signaling pathway.
化疗诱导的认知障碍（CICI）是与化疗药物使用相关的常见并发症。多柔比星（DOX）是一种产生活性氧物种（ROS）的抗癌药物，能够通过细胞因子诱导的氧化和硝化损伤脑组织而产生潜在的神经毒性作用。另一方面，α-硫辛酸（ALA）作为一种营养补充剂，以其出色的抗氧化、抗炎和抗细胞凋亡作用而广受赞誉。因此，本研究旨在探讨 ALA 是否具有神经保护和改善记忆的作用，以减轻 DOX 引起的行为和神经异常。DOX（2mg/kg/周，腹腔注射）每周给药 4 周，给 Sprague-Dawley 大鼠。给予 ALA（50、100 和 200mg/kg）4 周。使用 Morris 水迷宫（MWM）和新物体识别任务（NORT）测试评估记忆功能。使用紫外可见分光光度法的生化分析来分析氧化应激标志物[丙二醛（MDA）、蛋白羰基化（PCO）]、内源性抗氧化剂[还原型谷胱甘肽（GSH）、过氧化氢酶（CAT）、超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）]和海马组织中的乙酰胆碱酯酶（AChE）活性。使用酶联免疫吸附测定法（ELISA）评估炎症标志物[肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和核因子 kappa B（NF-κB）]、核因子红细胞 2 相关因子-2（NRF-2）和血红素加氧酶-1（HO-1）水平。此外，使用荧光法通过 2-7-二氯荧光素二乙酸酯（DCFH-DA）测定法测量海马组织中的活性氧（ROS）水平。ALA 治疗可显著防止 DOX 引起的记忆障碍。此外，ALA 通过上调 NRF-2/HO-1 水平来阻止 DOX 引起的氧化和炎症损伤，从而恢复海马抗氧化剂，并减轻 NF-κB 表达的增加。这些结果表明，ALA 通过 NRF-2/HO-1 信号通路提供了对 DOX 引起的认知障碍的神经保护作用，这可能归因于其抗氧化潜力。
