El-Mancy Eman M, Elsherbini Dalia Mahmoud Abdelmonem, Al-Serwi Rasha Hamed, El-Sherbiny Mohamed, Ahmed Shaker Gehan, Abdel-Moneim Abdel-Moneim Hafez, Enan Eman T, Elsherbiny Nehal M
Deanship of Common First Year, Jouf University, P.O. Box 2014, Sakaka 42421, Saudi Arabia.
Zoology Department, Faculty of Women for Arts, Science and Education, Ain Shams University, Cairo 11511, Egypt.
Toxics. 2022 Aug 2;10(8):442. doi: 10.3390/toxics10080442.
The clinical application of cyclosporine A (CsA) as an immunosuppressive agent is limited by its organ toxicity. We aimed to evaluate the effectiveness of α-lipoic acid against CsA-induced hepatotoxicity and to delineate the underlying molecular mechanisms. Male Wistar rats (n = 24, 8 per each group) received the vehicle, CsA (25 mg/kg) and/or ALA (100 mg/kg, p.o.) for 3 weeks. Biochemical markers of liver function (serum ALT, AST, ALP < GGT), oxidative stress (MDA, TAC, SOD, GSH, Nrf2/HO-1), inflammation (NF-κB, CD68, iNOS, NO, COX-2), and apoptosis (caspase-3) were assessed in serum and tissue. Liver histological analysis using H&E and Sirius red was performed. The development of liver injury in CsA-treated animals was indicated by elevated levels of liver enzymes, oxidants/antioxidants imbalance, inflammatory cells infiltration, up-regulated expression of inflammatory mediators, and apoptosis. These changes were associated with altered architecture of hepatic cells and fibrous connective tissue. ALA co-administration protected against CsA-induced liver damage and ameliorated biochemical changes and cellular injury. In conclusion, ALA demonstrated hepatoprotective potential against CsA-induced liver injury through combating oxidative stress, inflammation, and apoptosis, highlighting ALA as a valuable adjunct to CsA therapy.
环孢素A（CsA）作为一种免疫抑制剂，其临床应用受到器官毒性的限制。我们旨在评估α-硫辛酸对CsA诱导的肝毒性的有效性，并阐明其潜在的分子机制。雄性Wistar大鼠（n = 24，每组8只）接受赋形剂、CsA（25 mg/kg）和/或ALA（100 mg/kg，口服），持续3周。评估血清和组织中肝功能的生化标志物（血清ALT、AST、ALP < GGT）、氧化应激（MDA、TAC、SOD、GSH、Nrf2/HO-1）、炎症（NF-κB、CD68、iNOS、NO、COX-2）和凋亡（caspase-3）。使用苏木精和伊红以及天狼星红进行肝脏组织学分析。CsA处理的动物肝脏损伤的发展表现为肝酶水平升高、氧化剂/抗氧化剂失衡、炎性细胞浸润、炎症介质表达上调和凋亡。这些变化与肝细胞和纤维结缔组织的结构改变有关。联合使用ALA可预防CsA诱导的肝损伤，并改善生化变化和细胞损伤。总之，ALA通过对抗氧化应激、炎症和凋亡，对CsA诱导的肝损伤具有肝保护潜力，突出了ALA作为CsA治疗的有价值辅助药物的地位。
