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

Abstract

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 senescenceassociated 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. Senescenceassociated 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.

An integrated approach to identifying sex-specific genes, transcription factors, and pathways relevant to Alzheimer’s disease

“…Studies have associated additional components of this family with neuroinflammation, an early event in AD [108, 109]. TERF2 is “Repressed” in female AD patients and “Activated” in male AD patients and has been related to senescence in AD [110, 111]. Wu et al positively correlated the expression of TRF1 and TRF2 in AD patients with age and Tau protein levels in blood serum [112].…”

β‐Galactosidase: Insights into source variability, genetic engineering, immobilisation and diverse applications in food, industry and medicine

“…2021), neuronal cells (Wang et al . 2023), prostate cancer (Wagner et al . 2015) and in hepatocellular carcinoma (Tiwari et al .…”

Comment on: “Gout/hyperuricemia reduces the risk of Alzheimer's disease: A meta‐analysis based on latest evidence”

“…We read with great interest the recent systematic review and meta‐analysis by Wang et al. (2023), which explored the association of hyperuricemia and gout with Alzheimer's disease. The authors observed a negative correlation between the two conditions detected by a hazard ratio of 0.69 (95% confidence interval 0.66–0.72).…”