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REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats

REL-1017 (esmethadone; dextromethadone; (S)-methadone) is the opioid-inactive dextro-isomer of the racemic mixture, (R, S)-methadone. REL-1017 acts as a low affinity, low potency N-methyl-D-aspartate receptor (NMDAR) channel blocker with rapid, robust, and sustained therapeutic effects in patients w...

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Autores principales: Bifari, Francesco, Pappagallo, Marco, Bleavins, Michael, Traversa, Sergio, Folli, Franco, Manfredi, Paolo L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097919/
https://www.ncbi.nlm.nih.gov/pubmed/35571103
http://dx.doi.org/10.3389/fphar.2022.863959
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author Bifari, Francesco
Pappagallo, Marco
Bleavins, Michael
Traversa, Sergio
Folli, Franco
Manfredi, Paolo L.
author_facet Bifari, Francesco
Pappagallo, Marco
Bleavins, Michael
Traversa, Sergio
Folli, Franco
Manfredi, Paolo L.
author_sort Bifari, Francesco
collection PubMed
description REL-1017 (esmethadone; dextromethadone; (S)-methadone) is the opioid-inactive dextro-isomer of the racemic mixture, (R, S)-methadone. REL-1017 acts as a low affinity, low potency N-methyl-D-aspartate receptor (NMDAR) channel blocker with rapid, robust, and sustained therapeutic effects in patients with major depressive disorder (MDD). Systemic administration of NMDAR blockers may cause transient and reversible pathomorphological alterations in brain cortical neurons characterized by cytoplasmic vacuolization, which are called Olney’s lesions, and may also lead to irreversible neuronal necrosis. We determined whether REL-1017 administration via oral gavage for 1–4 days to Sprague-Dawley rats could produce Olney’s lesions and cortical neuronal death and microgliosis as compared with MK-801, a known neurotoxic potent NMDAR blocker. As previously reported, MK-801 produced Olney’s lesions, neuronal necrosis and cortical microgliosis, and impaired behavior and activity. In contrast, administration of REL-1017 at low (20–31.25 mg/kg in females and males), medium (40–62.5 mg/kg) or high (80–110 mg/kg) doses did not cause pathomorphological changes in brain neurons and did not cause impaired behavior and activity. In conclusion, REL-1017 did not produce initial or cumulative neurotoxic effects or other evidence of damage to cortical neurons, further encouraging the development of REL-1017 as a potentially safe novel candidate for rapid treatment of MDD.
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spelling pubmed-90979192022-05-13 REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats Bifari, Francesco Pappagallo, Marco Bleavins, Michael Traversa, Sergio Folli, Franco Manfredi, Paolo L. Front Pharmacol Pharmacology REL-1017 (esmethadone; dextromethadone; (S)-methadone) is the opioid-inactive dextro-isomer of the racemic mixture, (R, S)-methadone. REL-1017 acts as a low affinity, low potency N-methyl-D-aspartate receptor (NMDAR) channel blocker with rapid, robust, and sustained therapeutic effects in patients with major depressive disorder (MDD). Systemic administration of NMDAR blockers may cause transient and reversible pathomorphological alterations in brain cortical neurons characterized by cytoplasmic vacuolization, which are called Olney’s lesions, and may also lead to irreversible neuronal necrosis. We determined whether REL-1017 administration via oral gavage for 1–4 days to Sprague-Dawley rats could produce Olney’s lesions and cortical neuronal death and microgliosis as compared with MK-801, a known neurotoxic potent NMDAR blocker. As previously reported, MK-801 produced Olney’s lesions, neuronal necrosis and cortical microgliosis, and impaired behavior and activity. In contrast, administration of REL-1017 at low (20–31.25 mg/kg in females and males), medium (40–62.5 mg/kg) or high (80–110 mg/kg) doses did not cause pathomorphological changes in brain neurons and did not cause impaired behavior and activity. In conclusion, REL-1017 did not produce initial or cumulative neurotoxic effects or other evidence of damage to cortical neurons, further encouraging the development of REL-1017 as a potentially safe novel candidate for rapid treatment of MDD. Frontiers Media S.A. 2022-04-25 /pmc/articles/PMC9097919/ /pubmed/35571103 http://dx.doi.org/10.3389/fphar.2022.863959 Text en Copyright © 2022 Bifari, Pappagallo, Bleavins, Traversa, Folli and Manfredi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Bifari, Francesco
Pappagallo, Marco
Bleavins, Michael
Traversa, Sergio
Folli, Franco
Manfredi, Paolo L.
REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats
title REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats
title_full REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats
title_fullStr REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats
title_full_unstemmed REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats
title_short REL-1017 (Esmethadone), A Novel NMDAR Blocker for the Treatment of MDD is Not Neurotoxic in Sprague-Dawley Rats
title_sort rel-1017 (esmethadone), a novel nmdar blocker for the treatment of mdd is not neurotoxic in sprague-dawley rats
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9097919/
https://www.ncbi.nlm.nih.gov/pubmed/35571103
http://dx.doi.org/10.3389/fphar.2022.863959
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