Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like b...

Autores
Arena, Ángeles Romina; Rubinstein, Mara Roxana; Genaro, Ana María; Tifner, Vera; Risnik, Denise Mariel; López-Carvajal, Jhon Esteban; Daray, Federico Manuel; Carrera Silva, Eugenio Antonio; Errasti, Andrea Emilse
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Fil: Arena, Ángeles Romina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: Rubinstein, Mara Roxana. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Genaro, Ana María. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Tifner, Vera. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: Risnik, Denise Mariel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: López-Carvajal, Jhon Esteban. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: Daray, Federico Manuel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Errasti, Andrea Emilse. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Ketamine has emerged as a rapid and sustained treatment for Major Depressive Disorder (MDD) and an alternative for patients who have not responded to traditional therapies. Its effects have been partly attributed to the noncompetitive antagonism of the Nmethyl-D-aspartate receptor (NMDAR) in the central nervous system, which enhances neuroplasticity. However, the etiopathology of MDD is complex, and substantial evidence suggests that inflammation may significantly contribute to the initiation and maintenance of MDD. Furthermore, the rapid and sustained antidepressant effect of ketamine may be attributed to its antiinflammatory and immunomodulatory actions. To investigate the antidepressant and anti-inflammatory effect of ketamine, we used a lipopolysaccharide (LPS)-induced depressive-like murine model. The Tail Suspension Test (TST) and Sucrose Preference Test (SPT) were conducted to assess depressive-like behaviors. Additionally, cellular immunophenotyping of blood, spleen, and brain was performed by flow cytometry. Ketamine administration (10–20 mg/kg) alleviated despair and anhedonia in LPS-depressive-like mice, as evidenced by the TST and SPT tests. Behavioral changes were accompanied by the reduction of Ly6G+ neutrophils and an increment of anti-inflammatory Ly6Clow/neg monocytes in the blood. Ketamine treatment also reduced CD45highLy6GnegLy6Chigh monocyte infiltration into the brain and dampened microglial activation (CD45lowCD11bhigh). In the spleen, ketamine decreased the expansion of acute T lymphocyte response (CD3+ CD4negCD8neg) induced by LPS, while increasing the percentage of CD4+ CD69+ TIM-3+ lymphocytes, known for their regulatory function. Splenic macrophages were also polarized towards an antiinflammatory CD206+ M2-phenotype with ketamine. Finally, we showed that the anti-inflammatory and antidepressant effects are linked, perhaps as convergent outcomes, by using another NMDA receptor antagonist, MK-801, and the mTOR signaling inhibitor, rapamycin. These findings highlight ketamine’s multifaceted mechanisms of action, underscoring its potential as a treatment for MDD, particularly in patients with significant inflammation.
Fuente
Molecular Psychiatry, vol. 30, n. 1
Materia
KETAMINA
NEUROINFLAMACION
DEPRESION
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/4.0/
Repositorio
Repositorio Institucional (UCA)
Institución
Pontificia Universidad Católica Argentina
OAI Identificador
oai:ucacris:123456789/22006
Acceder
id RIUCA_253c3fdb98b57dc6b62aa5a00c6c6849
oai_identifier_str oai:ucacris:123456789/22006
network_acronym_str RIUCA
repository_id_str 2585
network_name_str Repositorio Institucional (UCA)
spelling Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in miceArena, Ángeles RominaRubinstein, Mara RoxanaGenaro, Ana MaríaTifner, VeraRisnik, Denise MarielLópez-Carvajal, Jhon EstebanDaray, Federico ManuelCarrera Silva, Eugenio AntonioErrasti, Andrea EmilseKETAMINANEUROINFLAMACIONDEPRESIONFil: Arena, Ángeles Romina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: Rubinstein, Mara Roxana. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Genaro, Ana María. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; ArgentinaFil: Tifner, Vera. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: Risnik, Denise Mariel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: López-Carvajal, Jhon Esteban. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: Daray, Federico Manuel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaFil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Errasti, Andrea Emilse. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; ArgentinaKetamine has emerged as a rapid and sustained treatment for Major Depressive Disorder (MDD) and an alternative for patients who have not responded to traditional therapies. Its effects have been partly attributed to the noncompetitive antagonism of the Nmethyl-D-aspartate receptor (NMDAR) in the central nervous system, which enhances neuroplasticity. However, the etiopathology of MDD is complex, and substantial evidence suggests that inflammation may significantly contribute to the initiation and maintenance of MDD. Furthermore, the rapid and sustained antidepressant effect of ketamine may be attributed to its antiinflammatory and immunomodulatory actions. To investigate the antidepressant and anti-inflammatory effect of ketamine, we used a lipopolysaccharide (LPS)-induced depressive-like murine model. The Tail Suspension Test (TST) and Sucrose Preference Test (SPT) were conducted to assess depressive-like behaviors. Additionally, cellular immunophenotyping of blood, spleen, and brain was performed by flow cytometry. Ketamine administration (10–20 mg/kg) alleviated despair and anhedonia in LPS-depressive-like mice, as evidenced by the TST and SPT tests. Behavioral changes were accompanied by the reduction of Ly6G+ neutrophils and an increment of anti-inflammatory Ly6Clow/neg monocytes in the blood. Ketamine treatment also reduced CD45highLy6GnegLy6Chigh monocyte infiltration into the brain and dampened microglial activation (CD45lowCD11bhigh). In the spleen, ketamine decreased the expansion of acute T lymphocyte response (CD3+ CD4negCD8neg) induced by LPS, while increasing the percentage of CD4+ CD69+ TIM-3+ lymphocytes, known for their regulatory function. Splenic macrophages were also polarized towards an antiinflammatory CD206+ M2-phenotype with ketamine. Finally, we showed that the anti-inflammatory and antidepressant effects are linked, perhaps as convergent outcomes, by using another NMDA receptor antagonist, MK-801, and the mTOR signaling inhibitor, rapamycin. These findings highlight ketamine’s multifaceted mechanisms of action, underscoring its potential as a treatment for MDD, particularly in patients with significant inflammation.Nature Portfolio2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfhttps://repositorio.uca.edu.ar/handle/123456789/220061359-418410.1038/s41380-025-03338-wMolecular Psychiatry, vol. 30, n. 1reponame:Repositorio Institucional (UCA)instname:Pontificia Universidad Católica Argentinaenginfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/4.0/2026-11-05T12:34:22Zoai:ucacris:123456789/22006instacron:UCAInstitucionalhttps://repositorio.uca.edu.ar/Universidad privadaNo correspondehttps://repositorio.uca.edu.ar/oaiclaudia_fernandez@uca.edu.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:25852026-11-05 12:34:22.376Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentinafalse
dc.title.none.fl_str_mv Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice
title Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice
spellingShingle Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice
Arena, Ángeles Romina
KETAMINA
NEUROINFLAMACION
DEPRESION
title_short Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice
title_full Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice
title_fullStr Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice
title_full_unstemmed Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice
title_sort Ketamine reduces microglial activation and brain monocyte infiltration and promotes peripheral regulatory immune cells, relieving lipopolysaccharide (LPS)-induced depressive-like behavior in mice
dc.creator.none.fl_str_mv Arena, Ángeles Romina
Rubinstein, Mara Roxana
Genaro, Ana María
Tifner, Vera
Risnik, Denise Mariel
López-Carvajal, Jhon Esteban
Daray, Federico Manuel
Carrera Silva, Eugenio Antonio
Errasti, Andrea Emilse
author Arena, Ángeles Romina
author_facet Arena, Ángeles Romina
Rubinstein, Mara Roxana
Genaro, Ana María
Tifner, Vera
Risnik, Denise Mariel
López-Carvajal, Jhon Esteban
Daray, Federico Manuel
Carrera Silva, Eugenio Antonio
Errasti, Andrea Emilse
author_role author
author2 Rubinstein, Mara Roxana
Genaro, Ana María
Tifner, Vera
Risnik, Denise Mariel
López-Carvajal, Jhon Esteban
Daray, Federico Manuel
Carrera Silva, Eugenio Antonio
Errasti, Andrea Emilse
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv KETAMINA
NEUROINFLAMACION
DEPRESION
topic KETAMINA
NEUROINFLAMACION
DEPRESION
dc.description.none.fl_txt_mv Fil: Arena, Ángeles Romina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: Rubinstein, Mara Roxana. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Genaro, Ana María. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Tifner, Vera. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: Risnik, Denise Mariel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: López-Carvajal, Jhon Esteban. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: Daray, Federico Manuel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Fil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Errasti, Andrea Emilse. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
Ketamine has emerged as a rapid and sustained treatment for Major Depressive Disorder (MDD) and an alternative for patients who have not responded to traditional therapies. Its effects have been partly attributed to the noncompetitive antagonism of the Nmethyl-D-aspartate receptor (NMDAR) in the central nervous system, which enhances neuroplasticity. However, the etiopathology of MDD is complex, and substantial evidence suggests that inflammation may significantly contribute to the initiation and maintenance of MDD. Furthermore, the rapid and sustained antidepressant effect of ketamine may be attributed to its antiinflammatory and immunomodulatory actions. To investigate the antidepressant and anti-inflammatory effect of ketamine, we used a lipopolysaccharide (LPS)-induced depressive-like murine model. The Tail Suspension Test (TST) and Sucrose Preference Test (SPT) were conducted to assess depressive-like behaviors. Additionally, cellular immunophenotyping of blood, spleen, and brain was performed by flow cytometry. Ketamine administration (10–20 mg/kg) alleviated despair and anhedonia in LPS-depressive-like mice, as evidenced by the TST and SPT tests. Behavioral changes were accompanied by the reduction of Ly6G+ neutrophils and an increment of anti-inflammatory Ly6Clow/neg monocytes in the blood. Ketamine treatment also reduced CD45highLy6GnegLy6Chigh monocyte infiltration into the brain and dampened microglial activation (CD45lowCD11bhigh). In the spleen, ketamine decreased the expansion of acute T lymphocyte response (CD3+ CD4negCD8neg) induced by LPS, while increasing the percentage of CD4+ CD69+ TIM-3+ lymphocytes, known for their regulatory function. Splenic macrophages were also polarized towards an antiinflammatory CD206+ M2-phenotype with ketamine. Finally, we showed that the anti-inflammatory and antidepressant effects are linked, perhaps as convergent outcomes, by using another NMDA receptor antagonist, MK-801, and the mTOR signaling inhibitor, rapamycin. These findings highlight ketamine’s multifaceted mechanisms of action, underscoring its potential as a treatment for MDD, particularly in patients with significant inflammation.
description Fil: Arena, Ángeles Romina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://repositorio.uca.edu.ar/handle/123456789/22006
1359-4184
10.1038/s41380-025-03338-w
url https://repositorio.uca.edu.ar/handle/123456789/22006
identifier_str_mv 1359-4184
10.1038/s41380-025-03338-w
dc.language.none.fl_str_mv eng
language eng
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/4.0/
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Portfolio
publisher.none.fl_str_mv Nature Portfolio
dc.source.none.fl_str_mv Molecular Psychiatry, vol. 30, n. 1
reponame:Repositorio Institucional (UCA)
instname:Pontificia Universidad Católica Argentina
reponame_str Repositorio Institucional (UCA)
collection Repositorio Institucional (UCA)
instname_str Pontificia Universidad Católica Argentina
repository.name.fl_str_mv Repositorio Institucional (UCA) - Pontificia Universidad Católica Argentina
repository.mail.fl_str_mv claudia_fernandez@uca.edu.ar
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score 12.823554

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