Department of Clinical Pharmacology, Faculty of Medicine, Fayoum University, Fayoum 63511, Egypt; Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 52571, Saudi Arabia.
Department of Histology, Faculty of Medicine, Fayoum University, Egypt.
Eur J Pharmacol. 2021 Dec 5;912:174511. doi: 10.1016/j.ejphar.2021.174511. Epub 2021 Sep 20.
Cognitive impairments such as dementia are considered the biggest challenges for public health. Benzodiazepines are often prescribed for treatment of anxiety disorder but they are associated with elevated risk of dementia. The present study has been designed to evaluate the neuroprotective effect of telmisartan and metformin on diazepam-induced cognitive dysfunction in mice. Piracetam was used as an established nootropic agent. Mice were divided into 8 groups, group1; control group which received normal saline. groups 2, 3 and 4 were received telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. group 5; DZP group that injected with diazepam 2.5 mg/kg, groups 6, 7 and 8 were received diazepam 2.5 mg/kg + telmisartan 0.3 mg/kg/day, metformin 100 mg/kg/day and piracetam 200 mg/kg/day respectively. All drugs were administrated for 15 successive days. Cognitive skills of the animals were examined with Elevated plus maze and Passive Shock Avoidance tests. Investigations of oxidative stress markers were performed. Gene expression levels of TNF-α, NFκB, Caspase 3 and AMPK were analyzed using RT-PCR. Histological and immunohistochemical techniques were performed in hippocampus using H&E, cresyl violet stain, anti GFAP and anti COX-2 immunostain. The study revealed that administration of diazepam increased initial and retention transfer latency as well as it decreased step down latency that means it caused memory impairment. There was a significant increase in hippocampal expression levels of TNF-α, NFκB, and Caspase 3 and downregulation of AMPK expression levels associated with increased neurodegeneration, astrocytes activation and COX-2 immunohistochemical staining. This study indicates that diazepam caused a decline in cognitive function depending on hippocampal activity. Telmisartan, a common antihypertensive agent and metformin, a traditional antidiabetic drug improved this cognitive dysfunction through their anti-oxidant and anti-inflammatory effect as they decreased initial and retention transfer latency as well as it increased step down latency. Also they decreased TNF-α, NFκB, and Caspase 3 and upregulated AMPK expression, moreover they ameliorated the hippocampal morphological alterations, GFAP and COX-2 immunoexpression.
认知障碍，如痴呆症，被认为是公共卫生面临的最大挑战。苯二氮䓬类药物常用于治疗焦虑症，但它们与痴呆症风险升高有关。本研究旨在评估替米沙坦和二甲双胍对小鼠地西泮诱导的认知功能障碍的神经保护作用。吡拉西坦被用作一种已确立的益智药。将小鼠分为 8 组，第 1 组为对照组，给予生理盐水；第 2、3 和 4 组分别给予替米沙坦 0.3mg/kg/天、二甲双胍 100mg/kg/天和吡拉西坦 200mg/kg/天；第 5 组为 DZP 组，给予地西泮 2.5mg/kg；第 6、7 和 8 组分别给予地西泮 2.5mg/kg+替米沙坦 0.3mg/kg/天、二甲双胍 100mg/kg/天和吡拉西坦 200mg/kg/天。所有药物连续 15 天给药。通过高架十字迷宫和被动回避测试检查动物的认知技能。进行氧化应激标志物的研究。使用 RT-PCR 分析 TNF-α、NFκB、Caspase 3 和 AMPK 的基因表达水平。使用 H&E、甲苯胺蓝染色、抗 GFAP 和抗 COX-2 免疫染色在海马体进行组织学和免疫组织化学技术。研究表明，地西泮给药会增加初始和保留转移潜伏期，同时降低步下潜伏期，这意味着它会导致记忆障碍。海马体中 TNF-α、NFκB 和 Caspase 3 的表达水平显著增加，AMPK 表达水平下调，与神经退行性变、星形胶质细胞激活和 COX-2 免疫组织化学染色增加有关。这项研究表明，地西泮会导致认知功能下降，这取决于海马体的活动。替米沙坦，一种常见的降压药，二甲双胍，一种传统的抗糖尿病药物，通过其抗氧化和抗炎作用改善了这种认知功能障碍，因为它们降低了初始和保留转移潜伏期，同时增加了步下潜伏期。它们还降低了 TNF-α、NFκB 和 Caspase 3 的表达水平，上调了 AMPK 的表达水平，此外，它们还改善了海马体的形态改变、GFAP 和 COX-2 的免疫表达。
