Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies

In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of mic...

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Detalles Bibliográficos
Autores: Artigas, Francesc, Celada, Pau, Bortolozzi, Analía
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/176419
Acceso en línea:http://hdl.handle.net/10261/176419
Access Level:acceso abierto
Palabra clave:Ketamine
MicroRNA
Prefrontal cortex
Small interfering RNA
RNA interference
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spelling Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategiesArtigas, FrancescCelada, PauBortolozzi, AnalíaKetamineMicroRNAPrefrontal cortexSmall interfering RNARNA interferenceIn the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals. The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2 S,6 S;2 R,6 R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis. We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine.Support from the following grants is acknowledged: SAF2015-68346-P, SAF2016-75797-R and Retos-Colaboración Subprogram RTC-2015–3309-1, MINECO co-financed by European Regional Development Fund - ERDF), UE (Ministry of Economy and Competitiveness and European Regional Development Fund), PI12/00156, PI16/00287 and PI13/01390 (Instituto de Salud Carlos III, co-financed by ERDF, "A way to build Europe"), and Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM. Support from the Generalitat de Catalunya (2014SGR798 and 2017SGR717) is also acknowledged.Peer reviewedElsevierMinisterio de Economía y Competitividad (España)European CommissionInstituto de Salud Carlos IIICentro de Investigación Biomédica en Red Salud Mental (España)Generalitat de CatalunyaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/176419reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-68346-Pinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-75797-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/RTC-2015-3309-1https://doi.org/10.1016/j.euroneuro.2018.01.005Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1764192026-05-22T06:33:51Z
dc.title.none.fl_str_mv Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies
title Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies
spellingShingle Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies
Artigas, Francesc
Ketamine
MicroRNA
Prefrontal cortex
Small interfering RNA
RNA interference
title_short Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies
title_full Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies
title_fullStr Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies
title_full_unstemmed Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies
title_sort Can we increase the speed and efficacy of antidepressant treatments? Part II. Glutamatergic and RNA interference strategies
dc.creator.none.fl_str_mv Artigas, Francesc
Celada, Pau
Bortolozzi, Analía
author Artigas, Francesc
author_facet Artigas, Francesc
Celada, Pau
Bortolozzi, Analía
author_role author
author2 Celada, Pau
Bortolozzi, Analía
author2_role author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
European Commission
Instituto de Salud Carlos III
Centro de Investigación Biomédica en Red Salud Mental (España)
Generalitat de Catalunya
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Ketamine
MicroRNA
Prefrontal cortex
Small interfering RNA
RNA interference
topic Ketamine
MicroRNA
Prefrontal cortex
Small interfering RNA
RNA interference
description In the second part we focus on two treatment strategies that may overcome the main limitations of current antidepressant drugs. First, we review the experimental and clinical evidence supporting the use of glutamatergic drugs as fast-acting antidepressants. Secondly, we review the involvement of microRNAs (miRNAs) in the pathophysiology of major depressive disorder (MDD) and the use of small RNAs (e.g.., small interfering RNAs or siRNAs) to knockdown genes in monoaminergic and non-monoaminergic neurons and induce antidepressant-like responses in experimental animals. The development of glutamatergic agents is a promising venue for antidepressant drug development, given the antidepressant properties of the non-competitive NMDA receptor antagonist ketamine. Its unique properties appear to result from the activation of AMPA receptors by a metabolite [(2 S,6 S;2 R,6 R)-hydroxynorketamine (HNK)] and mTOR signaling. These effects increase synaptogenesis in prefrontal cortical pyramidal neurons and enhance serotonergic neurotransmission via descending inputs to the raphe nuclei. This view is supported by the cancellation of ketamine's antidepressant-like effects by inhibition of serotonin synthesis. We also review existing evidence supporting the involvement of miRNAs in MDD and the preclinical use of RNA interference (RNAi) strategies to target genes involved in antidepressant response. Many miRNAs have been associated to MDD, some of which e.g., miR-135 targets genes involved in antidepressant actions. Likewise, SSRI-conjugated siRNA evokes faster and/or more effective antidepressant-like responses. Intranasal application of sertraline-conjugated siRNAs directed to 5-HT1A receptors and SERT evoked much faster changes of pre- and postsynaptic antidepressant markers than those produced by fluoxetine.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/176419
url http://hdl.handle.net/10261/176419
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2015-68346-P
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-75797-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/RTC-2015-3309-1
https://doi.org/10.1016/j.euroneuro.2018.01.005
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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