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Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling

This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esm...

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Autores principales: Stahl, Stephen M., De Martin, Sara, Mattarei, Andrea, Bettini, Ezio, Pani, Luca, Guidetti, Clotilde, Folli, Franco, de Somer, Marc, Traversa, Sergio, Inturrisi, Charles E., Pappagallo, Marco, Gentilucci, Marco, Alimonti, Andrea, Fava, Maurizio, Manfredi, Paolo L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9602945/
https://www.ncbi.nlm.nih.gov/pubmed/36293063
http://dx.doi.org/10.3390/ijms232012196
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author Stahl, Stephen M.
De Martin, Sara
Mattarei, Andrea
Bettini, Ezio
Pani, Luca
Guidetti, Clotilde
Folli, Franco
de Somer, Marc
Traversa, Sergio
Inturrisi, Charles E.
Pappagallo, Marco
Gentilucci, Marco
Alimonti, Andrea
Fava, Maurizio
Manfredi, Paolo L.
author_facet Stahl, Stephen M.
De Martin, Sara
Mattarei, Andrea
Bettini, Ezio
Pani, Luca
Guidetti, Clotilde
Folli, Franco
de Somer, Marc
Traversa, Sergio
Inturrisi, Charles E.
Pappagallo, Marco
Gentilucci, Marco
Alimonti, Andrea
Fava, Maurizio
Manfredi, Paolo L.
author_sort Stahl, Stephen M.
collection PubMed
description This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca(2+) currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca(2+) currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects.
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spelling pubmed-96029452022-10-27 Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling Stahl, Stephen M. De Martin, Sara Mattarei, Andrea Bettini, Ezio Pani, Luca Guidetti, Clotilde Folli, Franco de Somer, Marc Traversa, Sergio Inturrisi, Charles E. Pappagallo, Marco Gentilucci, Marco Alimonti, Andrea Fava, Maurizio Manfredi, Paolo L. Int J Mol Sci Perspective This article presents a mechanism of action hypothesis to explain the rapid antidepressant effects of esmethadone (REL-1017) and other uncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonists and presents a corresponding mechanism of disease hypothesis for major depressive disorder (MDD). Esmethadone and other uncompetitive NMDAR antagonists may restore physiological neural plasticity in animal models of depressive-like behavior and in patients with MDD via preferential tonic block of pathologically hyperactive GluN2D subtypes. Tonic Ca(2+) currents via GluN2D subtypes regulate the homeostatic availability of synaptic proteins. MDD and depressive behaviors may be determined by reduced homeostatic availability of synaptic proteins, due to upregulated tonic Ca(2+) currents through GluN2D subtypes. The preferential activity of low-potency NMDAR antagonists for GluN2D subtypes may explain their rapid antidepressant effects in the absence of dissociative side effects. MDPI 2022-10-13 /pmc/articles/PMC9602945/ /pubmed/36293063 http://dx.doi.org/10.3390/ijms232012196 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Perspective
Stahl, Stephen M.
De Martin, Sara
Mattarei, Andrea
Bettini, Ezio
Pani, Luca
Guidetti, Clotilde
Folli, Franco
de Somer, Marc
Traversa, Sergio
Inturrisi, Charles E.
Pappagallo, Marco
Gentilucci, Marco
Alimonti, Andrea
Fava, Maurizio
Manfredi, Paolo L.
Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling
title Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling
title_full Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling
title_fullStr Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling
title_full_unstemmed Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling
title_short Esmethadone (REL-1017) and Other Uncompetitive NMDAR Channel Blockers May Improve Mood Disorders via Modulation of Synaptic Kinase-Mediated Signaling
title_sort esmethadone (rel-1017) and other uncompetitive nmdar channel blockers may improve mood disorders via modulation of synaptic kinase-mediated signaling
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9602945/
https://www.ncbi.nlm.nih.gov/pubmed/36293063
http://dx.doi.org/10.3390/ijms232012196
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