Background: 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.
Aims: However, the effects of Midazolam in oligomerized Aβ1.42 -induced neurotoxicity have not been reported previously. Here, we investigate whether Midazolam possesses a beneficial effect against oligomerized Aβ1.42 in SH-SY5Y neuronal cells.
Materials and methods: Cellular senescence was assessed using senescence-associated β-galactosidase staining. Telomerase activity was measured using the TeloTAGGG Telomerase PCR ELISA.
Results: 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 Aβ1.42 significantly increased cellular senescence of SH-SY5Y cells, but it was significantly alleviated by Midazolam. Additionally, Midazolam restored the oligomerized Aβ1.42 -induced reduction of telomerase activity. Interestingly, we found that oligomerized Aβ1.42 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 Aβ1.42 on the hTERT and TERF2 gene expressions. Importantly, the presence of Midazolam attenuated Aβ1.42 -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 Aβ1.42 in neuronal senescence.
Conclusion: We conclude that the usage of Midazolam is a potential treatment strategy for AD.
Keywords: Alzheimer's disease; Midazolam; aging; oligomerized amyloid β; senescence.
© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.