Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies

MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or...

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Autores principales:	Paulina Cieślik, Anna Siekierzycka, Adrianna Radulska, Agata Płoska, Grzegorz Burnat, Piotr Brański, Leszek Kalinowski, Joanna M. Wierońska
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	MK-801 scopolamine L-arginine cGMP S-nitrosylation schizophrenia Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/a55160ef2c07461c89c00a8ebdeff007
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spelling	oai:doaj.org-article:a55160ef2c07461c89c00a8ebdeff0072021-11-25T17:55:00ZNitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies10.3390/ijms2222122821422-00671661-6596https://doaj.org/article/a55160ef2c07461c89c00a8ebdeff0072021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12282https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.Paulina CieślikAnna SiekierzyckaAdrianna RadulskaAgata PłoskaGrzegorz BurnatPiotr BrańskiLeszek KalinowskiJoanna M. WierońskaMDPI AGarticleMK-801scopolamineL-argininecGMPS-nitrosylationschizophreniaBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12282, p 12282 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	MK-801 scopolamine L-arginine cGMP S-nitrosylation schizophrenia Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	MK-801 scopolamine L-arginine cGMP S-nitrosylation schizophrenia Biology (General) QH301-705.5 Chemistry QD1-999 Paulina Cieślik Anna Siekierzycka Adrianna Radulska Agata Płoska Grzegorz Burnat Piotr Brański Leszek Kalinowski Joanna M. Wierońska Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies
description	MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.
format	article
author	Paulina Cieślik Anna Siekierzycka Adrianna Radulska Agata Płoska Grzegorz Burnat Piotr Brański Leszek Kalinowski Joanna M. Wierońska
author_facet	Paulina Cieślik Anna Siekierzycka Adrianna Radulska Agata Płoska Grzegorz Burnat Piotr Brański Leszek Kalinowski Joanna M. Wierońska
author_sort	Paulina Cieślik
title	Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies
title_short	Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies
title_full	Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies
title_fullStr	Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies
title_full_unstemmed	Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies
title_sort	nitric oxide-dependent mechanisms underlying mk-801- or scopolamine-induced memory dysfunction in animals: mechanistic studies
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a55160ef2c07461c89c00a8ebdeff007
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Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies

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