Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices

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...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Monika Balk, Harald Hentschke, Uwe Rudolph, Bernd Antkowiak, Berthold Drexler
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/369b1971f7f640e9b842c17fbe13f0a6
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:369b1971f7f640e9b842c17fbe13f0a6
record_format	dspace
spelling	oai:doaj.org-article:369b1971f7f640e9b842c17fbe13f0a62021-12-02T16:06:11ZDifferential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices10.1038/s41598-017-03154-52045-2322https://doaj.org/article/369b1971f7f640e9b842c17fbe13f0a62017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03154-5https://doaj.org/toc/2045-2322Abstract 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.Monika BalkHarald HentschkeUwe RudolphBernd AntkowiakBerthold DrexlerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Monika Balk Harald Hentschke Uwe Rudolph Bernd Antkowiak Berthold Drexler Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices
description	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.
format	article
author	Monika Balk Harald Hentschke Uwe Rudolph Bernd Antkowiak Berthold Drexler
author_facet	Monika Balk Harald Hentschke Uwe Rudolph Bernd Antkowiak Berthold Drexler
author_sort	Monika Balk
title	Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices
title_short	Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices
title_full	Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices
title_fullStr	Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices
title_full_unstemmed	Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices
title_sort	differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/369b1971f7f640e9b842c17fbe13f0a6
work_keys_str_mv	AT monikabalk differentialdepressionofneuronalnetworkactivitybymidazolamanditsmainmetabolite1hydroxymidazolaminculturedneocorticalslices AT haraldhentschke differentialdepressionofneuronalnetworkactivitybymidazolamanditsmainmetabolite1hydroxymidazolaminculturedneocorticalslices AT uwerudolph differentialdepressionofneuronalnetworkactivitybymidazolamanditsmainmetabolite1hydroxymidazolaminculturedneocorticalslices AT berndantkowiak differentialdepressionofneuronalnetworkactivitybymidazolamanditsmainmetabolite1hydroxymidazolaminculturedneocorticalslices AT bertholddrexler differentialdepressionofneuronalnetworkactivitybymidazolamanditsmainmetabolite1hydroxymidazolaminculturedneocorticalslices
_version_	1718385080159698944

Differential depression of neuronal network activity by midazolam and its main metabolite 1-hydroxymidazolam in cultured neocortical slices

Ejemplares similares