| Autor: |
Płoska A; Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, 7 Debinki Street, 80-211 Gdansk, Poland., Siekierzycka A; Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, 7 Debinki Street, 80-211 Gdansk, Poland., Cieślik P; Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland., Dobrucki LW; Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, 7 Debinki Street, 80-211 Gdansk, Poland.; Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.; Beckman Institute for Advanced Science and Technology, Urbana, IL 61801, USA.; Department of Biomedical and Translational Sciences, Carle-Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA., Kalinowski L; Department of Medical Laboratory Diagnostics-Fahrenheit Biobank BBMRI.pl, Medical University of Gdansk, 7 Debinki Street, 80-211 Gdansk, Poland.; BioTechMed Center, Department of Mechanics of Materials and Structures, Gdansk University of Technology, 11/12 Narutowicza Steet, 80-223 Gdansk, Poland., Wierońska JM; Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland. |
| Abstrakt: |
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. |
