Department of Pharmacology and Toxicology, Faculty of Pharmacy, Horus University, New Damietta, Egypt.
Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Inflammopharmacology. 2022 Oct;30(5):1871-1890. doi: 10.1007/s10787-022-01023-w. Epub 2022 Aug 3.
Tauopathy is a group of neurodegenerative diseases in which the pathogenesis processes are related to tau protein. The imbalances between the activities of kinases and phosphatases of tau protein lead to tau hyperphosphorylation and subsequent neurodegeneration. Numerous studies suggest a strong linkage between type 2 diabetes mellitus (T2D) and neurodegenerative diseases. Therefore, finding a drug with a dual therapeutic activity against T2D and neuroprotective will be a promising idea. Hence, the potential neuroprotective effect of Glimepiride (GPD) against tauopathy was evaluated in the current study.
P301S mice model was employed for tauopathy and C57BL/6 wild type mice (WT) was used as control. Phosphorylated and acetylated tau protein levels was assessed in cortex and hippocampus by western blot. Effect of GPD on tauopathy related enzymes, neuroinflammation, apoptotic markers were evaluated. Furthermore, the neuroprotective effects against anxiety like behavior and motor impairment was analyzed using Parallel rod floor and Open field tests.
GPD significantly ameliorates motor impairment, anxiety like behavior and neurodegeneration in P301S mice. Phosphorylated tau and acetylated tau were significantly decreased in both cortex and hippocampus of P301S mice via decreasing GSK3β, increasing ratio of phosphorylated-AKT to total-AKT, increasing PP2A and normalization of CDK5 levels. Furthermore, GPD treatment also decreased neuroinflammation and apoptosis by reducing NF-kB, TNF-α and caspase 3 levels.
The current data suggests that GPD exerts a protective effect against tauopathy, behavioural consequences, neurodegeneration, neuroinflammation and apoptosis. GPD is therefore a promising agent for the treatment of neurodegenerative diseases associated with tauopathy.
tau 病是一组与 tau 蛋白相关的神经退行性疾病。tau 蛋白激酶和磷酸酶活性的失衡导致 tau 过度磷酸化，随后发生神经退行性变。许多研究表明 2 型糖尿病（T2D）与神经退行性疾病之间存在很强的关联。因此，找到一种对 T2D 和神经保护具有双重治疗活性的药物将是一个有前途的想法。因此，本研究评估了格列美脲（GPD）对 tau 病的潜在神经保护作用。
采用 P301S 小鼠模型进行 tau 病研究，C57BL/6 野生型（WT）小鼠作为对照。通过 Western blot 检测皮质和海马中的磷酸化和乙酰化 tau 蛋白水平。评估 GPD 对 tau 病相关酶、神经炎症、凋亡标志物的影响。此外，通过平行棒地板和旷场试验分析对焦虑样行为和运动障碍的神经保护作用。
GPD 可显著改善 P301S 小鼠的运动障碍、焦虑样行为和神经退行性变。通过降低 GSK3β、增加磷酸化-AKT 与总-AKT 的比值、增加 PP2A 和使 CDK5 水平正常化，可显著降低 P301S 小鼠皮质和海马中的磷酸化 tau 和乙酰化 tau。此外，GPD 治疗还通过降低 NF-kB、TNF-α 和 caspase 3 水平来减少神经炎症和凋亡。
目前的数据表明，GPD 对 tau 病、行为后果、神经退行性变、神经炎症和凋亡具有保护作用。因此，GPD 是治疗与 tau 病相关的神经退行性疾病的有前途的药物。
