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 beta (A beta)-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 A beta(1.42)-induced neurotoxicity have not been reported previously. Here, we investigate whether Midazolam possesses a beneficial effect against oligomerized A beta(1.42) in SH-SY5Y neuronal cells. Materials and Methods: Cellular senescence was assessed using senescence-associated beta-galactosidase staining. Telomerase activity was measured using the TeloTAGGG Telomerase PCR ELISA. Results: First, the lactate dehydrogenase release assay demonstrates that 10 and 20 mu M are the optimal concentrations of Midazolam used for cell cultures. Senescence-associated beta-galactosidase staining results indicate that exposure to oligomerized A beta(1.42) significantly increased cellular senescence of SH-SY5Y cells, but it was significantly alleviated by Midazolam. Additionally, Midazolam restored the oligomerized A beta(1.42)-induced reduction of telomerase activity. Interestingly, we found that oligomerized A beta(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 A beta(1.42) on the hTERT and TERF2 gene expressions. Importantly, the presence of Midazolam attenuated A beta(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 A beta(1.42) in neuronal senescence. Conclusion: We conclude that the usage of Midazolam is a potential treatment strategy for AD.