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Differential Depression of Neuronal Network Activity by Midazolam and Its Main Metabolite 1-hydroxymidazolam in Cultured Neocortical Slices

Differential Depression of Neuronal Network Activity by Midazolam and Its Main Metabolite 1-hydroxymidazolam in Cultured Neocortical Slices

Monika Balk, Harald Hentschke, Uwe Rudolph, Bernd Antkowiak, Berthold Drexler

Sci Rep. 2017 Jun 14;7(1):3503.

PMID: 28615640

Abstract:

The benzodiazepine midazolam is widely used in critical care medicine. Midazolam has a clinically active metabolite, 1-hydroxymidazolam. The contribution of 1-hydroxymidazolam to the effects of midazolam is controversial. The aim of the current study was to compare the actions of midazolam and 1-hydroxymidazolam on network activity of cortical neurons. Midazolam depressed neuronal activity at a low concentration of 5 nM. When midazolam concentration was increased, it depressed neuronal discharge rates in a biphasic manner. In comparison, 1-hydroxymidazolam did not depress the cortical network activity at low nanomolar concentrations. Higher concentrations of 1-hydroxymidazolam consistently inhibited neuronal activity. Moreover, midazolam shortened cortical up states at low, but not at high concentrations, while the opposite effect was observed with 1-hydroxymidazolam. The network depressant action of midazolam at low concentrations was absent in slices from GABAA receptor α1(H101R)mutant mice. The α1(H101R)mutation renders α1-subunit containing GABAA receptors insensitive towards benzodiazepines. This GABAA receptor subtype is thought to mediate sedation. As midazolam is more potent than its metabolite 1-hydroxymidazolam, the major clinical effects are thus likely caused by midazolam itself. However, 1-hydroxymidazolam could add to the effects of midazolam, especially after the application of high doses of midazolam, and in case of impaired drug metabolism.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP59468905-B	1′-Hydroxymidazolam		59468-90-5	Price

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