In:
PLOS ONE, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2022-7-8), p. e0271119-
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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0271119
DOI:
10.1371/journal.pone.0271119.g001
DOI:
10.1371/journal.pone.0271119.g002
DOI:
10.1371/journal.pone.0271119.g003
DOI:
10.1371/journal.pone.0271119.g004
DOI:
10.1371/journal.pone.0271119.g005
DOI:
10.1371/journal.pone.0271119.t001
DOI:
10.1371/journal.pone.0271119.s001
DOI:
10.1371/journal.pone.0271119.s002
DOI:
10.1371/journal.pone.0271119.r001
DOI:
10.1371/journal.pone.0271119.r002
DOI:
10.1371/journal.pone.0271119.r003
DOI:
10.1371/journal.pone.0271119.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2267670-3
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