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The Impact of LY487379 or CDPPB on eNOS Expression in the Mouse Brain and the Effect of Joint Administration of Compounds with NO• Releasers on MK-801- or Scopolamine-Driven Cognitive Dysfunction in Mice
Abstract
The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer’s disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO• donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD.
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Authors (6)
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Agata Płoska
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Anna Siekierzycka
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Paulina Cieślik
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Lawrence W. Dobrucki
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Joanna M. Wierońska
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- Accepted or Published Version
- DOI:
- Digital Object Identifier (open in new tab) 10.3390/molecules29030627
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- Category:
- Articles
- Type:
- artykuły w czasopismach
- Published in:
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MOLECULES
no. 29,
ISSN: 1420-3049 - Language:
- English
- Publication year:
- 2024
- Bibliographic description:
- Płoska A., Siekierzycka A., Cieślik P., Dobrucki L. W., Kalinowski L., Wierońska J. M.: The Impact of LY487379 or CDPPB on eNOS Expression in the Mouse Brain and the Effect of Joint Administration of Compounds with NO• Releasers on MK-801- or Scopolamine-Driven Cognitive Dysfunction in Mice// MOLECULES -Vol. 29,iss. 3 (2024), s.627-
- DOI:
- Digital Object Identifier (open in new tab) 10.3390/molecules29030627
- Sources of funding:
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- This research was funded by the National Science Center, grant no. 2019/33/B/NZ7/02699 (OPUS 17), and the Ministry of Education and Science, grant no. 2/566516/SPUB/SP/2023.
- Verified by:
- Gdańsk University of Technology
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