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Cieślik P, Siekierzycka A, Radulska A, et al. Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies. Int J Mol Sci. 2021;22(22)doi: 10.3390/ijms222212282.
Cieślik, P., Siekierzycka, A., Radulska, A., Płoska, A., Burnat, G., Brański, P., Kalinowski, L., & Wierońska, J. M. (2021). Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies. International journal of molecular sciences, 22(22), . https://doi.org/10.3390/ijms222212282
Cieślik, Paulina, et al. "Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies." International journal of molecular sciences vol. 22,22 (2021). doi: https://doi.org/10.3390/ijms222212282
Cieślik P, Siekierzycka A, Radulska A, Płoska A, Burnat G, Brański P, Kalinowski L, Wierońska JM. Nitric Oxide-Dependent Mechanisms Underlying MK-801- or Scopolamine-Induced Memory Dysfunction in Animals: Mechanistic Studies. Int J Mol Sci. 2021 Nov 13;22(22). doi: 10.3390/ijms222212282. PMID: 34830164; PMCID: PMC8624219.
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Int J Mol Sci. 2021 Nov 13;22(22). doi: 10.3390/ijms222212282.

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

International journal of molecular sciences

Paulina Cieślik, Anna Siekierzycka, Adrianna Radulska, Agata Płoska, Grzegorz Burnat, Piotr Brański, Leszek Kalinowski, Joanna M Wierońska

Affiliations

  1. Department of Neurobiology, Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Sm?tna Street, 31-343 Kraków, Poland.
  2. Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI.pl, Medical University of Gda?sk, 7 D?binki Street, 80-211 Gda?sk, Poland.
  3. Biobanking and Biomoleclular Resources Research Infrastructure Consortium Poland (BBMRI.pl), 7 D?binki Street, 80-211 Gda?sk, Poland.
  4. BioTechMed Centre, Department of Mechanics of Materials and Structures, University of Technology, 11/12 Narutowicza, 80-233 Gda?sk, Poland.

PMID: 34830164 PMCID: PMC8624219 DOI: 10.3390/ijms222212282

Abstract

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.

Keywords: ADMA; Alzheimer’s disease; DDAH1; L-arginine; MK-801; NMMA; S-nitrosylation; SDAMA; cGMP; schizophrenia; scopolamine

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