Doghaither Huda A Al, Elmorsy Ekramy Mahmoud
Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Int J Health Sci (Qassim). 2023 Jul-Aug;17(4):11-21.
The study aims to assess apoptosis, oxidative stress, and inflammation as underlying diabetogenic mechanisms in isolated CD1 mouse beta-pancreatic cells of some prescribed Antipsychotics (APs).
Three types of APs were tested in different concentrations (0.1, 1, 10, and 100 μM) on adult male CD1 mice. The cytotoxicity of the tested APs was determined using different assays including MTT and Lactate Dehydrogenase (LDH) assays. Oxidative stress was assessed by and measuring Reactive oxygen species (ROS) production, lipid peroxidation, and antioxidant enzyme activities. Moreover, the effect on the inflammatory cascade was also investigated.
The tested APs were cytotoxic to beta cells and showed patterns dependent on both concentration and exposure, with a parallel reduction in glucose-stimulated insulin secretion of the treated cells. The APs also showed induction of oxidative stress in the treated cells by significantly increasing the ROS, lipid peroxidation, and NRf2 gene expression, together with decreased antioxidant enzyme activities. Moreover, APs showed significant increases in cytokines levels to their estimated IC50 levels. The activities of caspases 3, 8, and 9 were also significantly increased in all treated samples at their IC50s and at 10 μM concentrations of all tested APs. However, the glutathione and inhibitors of caspase-3, IL-6, and TNF-α significantly improved GSIS and the viability of the AP-treated cells.
The results suggest a significant role for apoptosis, oxidative stress, and inflammation, in the diabetogenic effect of APs, expected role of antioxidants and anti-inflammatory drugs as therapeutics for improving the outcome in cases of long-term prescribed APs.
本研究旨在评估凋亡、氧化应激和炎症作为某些处方抗精神病药物（APs）在分离的成年雄性CD1小鼠胰腺β细胞中致糖尿病机制的潜在因素。
对成年雄性CD1小鼠测试三种不同浓度（0.1、1、10和100μM）的APs。使用包括MTT和乳酸脱氢酶（LDH）测定在内的不同测定方法确定测试APs的细胞毒性。通过测量活性氧（ROS）生成、脂质过氧化和抗氧化酶活性来评估氧化应激。此外，还研究了对炎症级联反应的影响。
测试的APs对β细胞具有细胞毒性，并呈现出浓度和暴露时间依赖性模式，同时处理细胞的葡萄糖刺激胰岛素分泌平行降低。APs还通过显著增加ROS、脂质过氧化和NRf2基因表达以及降低抗氧化酶活性，在处理细胞中诱导氧化应激。此外，APs在达到其估计的半数抑制浓度（IC50）时细胞因子水平显著升高。在所有测试APs的IC50和10μM浓度下，所有处理样本中半胱天冬酶3、8和9的活性也显著增加。然而，谷胱甘肽以及半胱天冬酶 - 3、白细胞介素 - 6和肿瘤坏死因子 - α的抑制剂显著改善了葡萄糖刺激的胰岛素分泌（GSIS）以及AP处理细胞的活力。
结果表明凋亡、氧化应激和炎症在APs的致糖尿病作用中起重要作用，抗氧化剂和抗炎药物有望作为治疗药物改善长期使用APs病例的预后。
