Midazolam impacts acetyl—And butyrylcholinesterase genes: An epigenetic explanation for postoperative delirium?

Abstract

Midazolam is a widely used short-acting benzodiazepine. However, midazolam is also criticized for its deliriogenic potential. Since delirium is associated with a malfunction of the neurotransmitter acetylcholine, midazolam appears to interfere with its proper metabolism, which can be triggered by epigenetic modifications. Consequently, we tested the hypothesis that midazolam indeed changes the expression and activity of cholinergic genes by acetylcholinesterase assay and qPCR. Furthermore, we investigated the occurrence of changes in the epigenetic landscape by methylation specific PCR, ChiP-Assay and histone ELISA. In an in-vitro model containing SH-SY5Y neuroblastoma cells, U343 glioblastoma cells, and human peripheral blood mononuclear cells, we found that midazolam altered the activity of acetylcholinesterase /buturylcholinesterase (AChE / BChE). Interestingly, the increased expression of the buturylcholinesterase evoked by midazolam was accompanied by a reduced methylation of the BCHE gene and the di-methylation of histone 3 lysine 4 and came along with an increased expression of the lysine specific demethylase KDM1A. Last, inflammatory cytokines were not induced by midazolam. In conclusion, we found a promising mechanistic link between midazolam treatment and delirium, due to a significant disruption in cholinesterase homeostasis. In addition, midazolam seems to provoke profound changes in the epigenetic landscape. Therefore, our results can contribute to a better understanding of the hitherto poorly understood interactions and risk factors of midazolam on delirium.

Postoperative delirium in geriatric patients with hip fractures

“…However, numerous studies have demonstrated that perioperative usage of BZDRAs is linked to a higher risk of POD in geriatric patients with hip fractures ( Poeran et al, 2020 ; Hernandez et al, 2021 ; Duprey et al, 2022 ; Lertkovit et al, 2022 ). The concrete mechanisms of benzodiazepine-induced POD vary based on the subtype of BZDRAs: Diazepam may affect the chloride plasticity mediated by Na + − K + − 2Cl-cotransporter isoform 1 and result in the gamma-aminobutyric acid α receptor malfunction ( Matsumoto et al, 2021 ); midazolam can alter the expression and activity of acetyl-and butyryl-cholinesterase genes ( Rump et al, 2022 ), and both contribute to benzodiazepine - induced POD. Additionally, a retrospective cohort study of 250 patients who were scheduled for surgery under general anesthesia investigated the relationship between the time course of BZDRAs use and the incidence of POD.…”

Postoperative delirium, neuroinflammation, and influencing factors of postoperative delirium: A review

“…[48] Although the effect of midazolam on POD does not appear to be mediated by inflammatory signaling pathways, it may be related to cholinesterase genes. [49] Recently, the use of a new benzodiazepine, remimazolam, was found to reduce the incidence of POD in cardiac surgery. [50] Remimazolam, an ultrashort-acting benzodiazepine, ameliorated the LPS-induced peripheral blood septic response in mice, reduced the number of LPS-induced deaths, and decreased the production of inflammatory factors in cultured macrophages in vitro.…”

CABG Patients Develop Global DNA Hypermethylation, That Negatively Affect the Mitochondrial Function and Promote Post-Surgical Cognitive Decline: A Proof of Concept in Small Cohort

“…On the contrary, propofol and isoflurane anesthetics were found to unalter the leukocyte DNA methylation according to a recent study [ 33 ], suggesting that more studies are required in this direction to unfold the underlying mechanism behind the role of anesthesia on the surgery-induced DNMT changes and consecutive MCI. However among the five different anesthetics (propofol, sodium thiopental, midazolam, fentanyl, vecuronium) used in the present study for the surgery, three anesthetics propofol [ 34 ], midazolam [ 35 ] and fentanyl [ 36 ] are reported to alter methylation level and its gene expression, therefore this 61% increase in methylation in post-surgical MCI cases may be the cumulative impact of anesthesia and surgery. However, no significant correlation was observed between the specific anesthesia, methylation, and MoCA score in the present study.…”