Midazolam alleviates cellular senescence in SH‐SY5Y neuronal cells in Alzheimer's disease

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 Aβ(1.42)‐induced neurotoxicity have not been reported previously. Here, we investigate whether Midazolam possesses a beneficial effect against oligomerized Aβ(1.42) 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 Aβ(1.42) significantly increased cellular senescence of SH‐SY5Y cells, but it was significantly alleviated by Midazolam. Additionally, Midazolam restored the oligomerized Aβ(1.42)‐induced reduction of telomerase activity. Interestingly, we found that oligomerized Aβ(1.42) 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 Aβ(1.42) on the hTERT and TERF2 gene expressions. Importantly, the presence of Midazolam attenuated Aβ(1.42)‐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 Aβ(1.42) in neuronal senescence. CONCLUSION: We conclude that the usage of Midazolam is a potential treatment strategy for AD.