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Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors

Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effe...

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Autores principales: Estrada-Reyes, Rosa, Quero-Chávez, Daniel B., Alarcón-Elizalde, Salvador, Cercós, Montserrat G., Trueta, Citlali, Constantino-Jonapa, Luis A., Oikawa-Sala, Julián, Argueta, Jesús, Cruz-Garduño, Ricardo, Dubocovich, Margarita L., Benítez-King, Gloria A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9458007/
https://www.ncbi.nlm.nih.gov/pubmed/36080418
http://dx.doi.org/10.3390/molecules27175650
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author Estrada-Reyes, Rosa
Quero-Chávez, Daniel B.
Alarcón-Elizalde, Salvador
Cercós, Montserrat G.
Trueta, Citlali
Constantino-Jonapa, Luis A.
Oikawa-Sala, Julián
Argueta, Jesús
Cruz-Garduño, Ricardo
Dubocovich, Margarita L.
Benítez-King, Gloria A.
author_facet Estrada-Reyes, Rosa
Quero-Chávez, Daniel B.
Alarcón-Elizalde, Salvador
Cercós, Montserrat G.
Trueta, Citlali
Constantino-Jonapa, Luis A.
Oikawa-Sala, Julián
Argueta, Jesús
Cruz-Garduño, Ricardo
Dubocovich, Margarita L.
Benítez-King, Gloria A.
author_sort Estrada-Reyes, Rosa
collection PubMed
description Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.
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spelling pubmed-94580072022-09-09 Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors Estrada-Reyes, Rosa Quero-Chávez, Daniel B. Alarcón-Elizalde, Salvador Cercós, Montserrat G. Trueta, Citlali Constantino-Jonapa, Luis A. Oikawa-Sala, Julián Argueta, Jesús Cruz-Garduño, Ricardo Dubocovich, Margarita L. Benítez-King, Gloria A. Molecules Article Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression. MDPI 2022-09-01 /pmc/articles/PMC9458007/ /pubmed/36080418 http://dx.doi.org/10.3390/molecules27175650 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 Article
Estrada-Reyes, Rosa
Quero-Chávez, Daniel B.
Alarcón-Elizalde, Salvador
Cercós, Montserrat G.
Trueta, Citlali
Constantino-Jonapa, Luis A.
Oikawa-Sala, Julián
Argueta, Jesús
Cruz-Garduño, Ricardo
Dubocovich, Margarita L.
Benítez-King, Gloria A.
Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors
title Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors
title_full Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors
title_fullStr Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors
title_full_unstemmed Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors
title_short Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors
title_sort antidepressant low doses of ketamine and melatonin in combination produce additive neurogenesis in human olfactory neuronal precursors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9458007/
https://www.ncbi.nlm.nih.gov/pubmed/36080418
http://dx.doi.org/10.3390/molecules27175650
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