Department of Anesthesiology, The First People's Hospital of Lianyungang, Xuzhou Medical University Affiliated Hospital of Lianyungang, Lianyungang, Jiangsu, China.
Brain Behav. 2023 Jan;13(1):e2822. doi: 10.1002/brb3.2822. Epub 2022 Nov 28.
Alzheimer's disease (AD) impacts the daily life of aging people. Oligomerized amyloid β (Aβ)-associated neuronal senescence is involved in the pathological mechanism of AD. Blockage of neuronal senescence has been considered an important strategy for the treatment of AD. Midazolam is a hypnotic-sedative drug with pleiotropic properties.
However, the effects of Midazolam in oligomerized Aβ -induced neurotoxicity have not been reported previously. Here, we investigate whether Midazolam possesses a beneficial effect against oligomerized Aβ in SH-SY5Y neuronal cells.
Cellular senescence was assessed using senescence-associated β-galactosidase staining. Telomerase activity was measured using the TeloTAGGG Telomerase PCR ELISA.
First, the lactate dehydrogenase release assay demonstrates that 10 and 20 µM are the optimal concentrations of Midazolam used for cell cultures. Senescence-associated β-galactosidase staining results indicate that exposure to oligomerized Aβ significantly increased cellular senescence of SH-SY5Y cells, but it was significantly alleviated by Midazolam. Additionally, Midazolam restored the oligomerized Aβ -induced reduction of telomerase activity. Interestingly, we found that oligomerized Aβ remarkably reduced human telomerase reverse transcriptase (hTERT) gene expression but increased the telomeric repeat-binding factor 2 (TERF2) expression. However, treatment with Midazolam reversed the effects of oligomerized Aβ on the hTERT and TERF2 gene expressions. Importantly, the presence of Midazolam attenuated Aβ -induced p53 and p21 expressions. Mechanistically, Midazolam repressed the level of cyclooxygenase-2 (COX-2) and the release of prostaglandin E2. Importantly, overexpression of COX-2 abolished the impact of Midazolam against oligomerized Aβ in neuronal senescence.
We conclude that the usage of Midazolam is a potential treatment strategy for AD.
阿尔茨海默病（AD）影响着老年人的日常生活。寡聚淀粉样β（Aβ）相关的神经元衰老与 AD 的病理机制有关。阻止神经元衰老已被认为是治疗 AD 的重要策略。咪达唑仑是一种具有多种特性的催眠镇静药物。
然而，咪达唑仑在寡聚 Aβ诱导的神经毒性中的作用以前尚未报道。在这里，我们研究咪达唑仑是否对 SH-SY5Y 神经元细胞中的寡聚 Aβ具有有益作用。
通过衰老相关β-半乳糖苷酶染色评估细胞衰老。使用 TeloTAGGG 端粒酶 PCR ELISA 测定端粒酶活性。
首先，乳酸脱氢酶释放测定表明，10 和 20 μM 是用于细胞培养的咪达唑仑最佳浓度。衰老相关β-半乳糖苷酶染色结果表明，寡聚 Aβ 显著增加了 SH-SY5Y 细胞的细胞衰老，但咪达唑仑明显减轻了这种衰老。此外，咪达唑仑恢复了寡聚 Aβ 诱导的端粒酶活性降低。有趣的是，我们发现寡聚 Aβ 显著降低了人端粒酶逆转录酶（hTERT）基因表达，但增加了端粒重复结合因子 2（TERF2）的表达。然而，用咪达唑仑处理可逆转寡聚 Aβ 对 hTERT 和 TERF2 基因表达的影响。重要的是，咪达唑仑减弱了 Aβ 诱导的 p53 和 p21 表达。在机制上，咪达唑仑抑制了环氧化酶-2（COX-2）的水平和前列腺素 E2 的释放。重要的是，COX-2 的过表达消除了咪达唑仑对神经元衰老中寡聚 Aβ的影响。
我们的结论是，使用咪达唑仑是治疗 AD 的一种潜在治疗策略。
