Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives

Autores
Tourville, Aurore; Viguier, Sarah; González Lizarraga, Maria Florencia; Tomas Grau, Rodrigo Hernán; Ramirez, Paola; Brunel, Jean Michel; Dos Santos Pereira, Mauricio; Del Bel, Elaine; Chehin, Rosana Nieves; Ferrié, Laurent; Raisman Vozari, Rita; Figadère, Bruno; Michel, Patrick Pierre
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Several studies have reported that the tetracycline (TC) class antibiotic doxycycline (DOX) is effective against Parkinson?s disease (PD) pathomechanisms. The aim of the present work was three-fold: (i) Establish a model system to better characterize neuroprotection by DOX; (ii) Compare the rescue effect of DOX to that of other TC antibiotics; (iii) Discover novel neuroprotective TCs having reduced antibiotic activity. For that, we used cultures of mouse midbrain dopamine (DA) neurons and experimental conditions that model iron-mediated oxidative damage, a key mechanism in PD pathobiology. We found that DOX and the other TC antibiotic, demeclocycline (DMC), provided sustained protection to DA neurons enduring iron-mediated insults, whereas chlortetracycline and non-TC class antibiotics did not. Most interestingly, non-antibiotic derivatives of DOX and DMC, i.e., DDOX and DDMC, respectively, were also robustly protective for DA neurons. Interestingly, DOX, DDOX, DMC, and DDMC remained protective for DA neurons until advanced stages of neurodegeneration, and the rescue effects of TCs were observable regardless of the degree of maturity of midbrain cultures. Live imaging studies with the fluorogenic probes DHR-123 and TMRM revealed that protective TCs operated by preventing intracellular oxidative stress and mitochondrial membrane depolarization, i.e., cellular perturbations occurring in this model system as the ultimate consequence of ferroptosis-mediated lipid peroxidation. If oxidative/mitochondrial insults were generated acutely, DOX, DDOX, DMC, and DDMC were no longer neuroprotective, suggesting that these compounds are mostly effective when neuronal damage is chronic and of low-intensity. Overall, our data suggest that TC derivatives, particularly those lacking antibiotic activity, might be of potential therapeutic utility to combat low-level oxidative insults that develop chronically in the course of PD neurodegeneration.
Fil: Tourville, Aurore. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
Fil: Viguier, Sarah. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
Fil: González Lizarraga, Maria Florencia. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Tomas Grau, Rodrigo Hernán. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Ramirez, Paola. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
Fil: Brunel, Jean Michel. Universite Paris-Saclay ;
Fil: Dos Santos Pereira, Mauricio. No especifíca;
Fil: Del Bel, Elaine. No especifíca;
Fil: Chehin, Rosana Nieves. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Ferrié, Laurent. Universite Paris-Saclay ;
Fil: Raisman Vozari, Rita. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
Fil: Figadère, Bruno. Universite Paris-Saclay ;
Fil: Michel, Patrick Pierre. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
Materia
DOPAMINE NEURONS
PARKINSON'S DISEASE
FERROPTOSIS
TETRACYCLINES
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/233552
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic DerivativesTourville, AuroreViguier, SarahGonzález Lizarraga, Maria FlorenciaTomas Grau, Rodrigo HernánRamirez, PaolaBrunel, Jean MichelDos Santos Pereira, MauricioDel Bel, ElaineChehin, Rosana NievesFerrié, LaurentRaisman Vozari, RitaFigadère, BrunoMichel, Patrick PierreDOPAMINE NEURONSPARKINSON'S DISEASEFERROPTOSISTETRACYCLINEShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Several studies have reported that the tetracycline (TC) class antibiotic doxycycline (DOX) is effective against Parkinson?s disease (PD) pathomechanisms. The aim of the present work was three-fold: (i) Establish a model system to better characterize neuroprotection by DOX; (ii) Compare the rescue effect of DOX to that of other TC antibiotics; (iii) Discover novel neuroprotective TCs having reduced antibiotic activity. For that, we used cultures of mouse midbrain dopamine (DA) neurons and experimental conditions that model iron-mediated oxidative damage, a key mechanism in PD pathobiology. We found that DOX and the other TC antibiotic, demeclocycline (DMC), provided sustained protection to DA neurons enduring iron-mediated insults, whereas chlortetracycline and non-TC class antibiotics did not. Most interestingly, non-antibiotic derivatives of DOX and DMC, i.e., DDOX and DDMC, respectively, were also robustly protective for DA neurons. Interestingly, DOX, DDOX, DMC, and DDMC remained protective for DA neurons until advanced stages of neurodegeneration, and the rescue effects of TCs were observable regardless of the degree of maturity of midbrain cultures. Live imaging studies with the fluorogenic probes DHR-123 and TMRM revealed that protective TCs operated by preventing intracellular oxidative stress and mitochondrial membrane depolarization, i.e., cellular perturbations occurring in this model system as the ultimate consequence of ferroptosis-mediated lipid peroxidation. If oxidative/mitochondrial insults were generated acutely, DOX, DDOX, DMC, and DDMC were no longer neuroprotective, suggesting that these compounds are mostly effective when neuronal damage is chronic and of low-intensity. Overall, our data suggest that TC derivatives, particularly those lacking antibiotic activity, might be of potential therapeutic utility to combat low-level oxidative insults that develop chronically in the course of PD neurodegeneration.Fil: Tourville, Aurore. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; FranciaFil: Viguier, Sarah. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; FranciaFil: González Lizarraga, Maria Florencia. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; ArgentinaFil: Tomas Grau, Rodrigo Hernán. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; ArgentinaFil: Ramirez, Paola. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; FranciaFil: Brunel, Jean Michel. Universite Paris-Saclay ;Fil: Dos Santos Pereira, Mauricio. No especifíca;Fil: Del Bel, Elaine. No especifíca;Fil: Chehin, Rosana Nieves. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; ArgentinaFil: Ferrié, Laurent. Universite Paris-Saclay ;Fil: Raisman Vozari, Rita. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; FranciaFil: Figadère, Bruno. Universite Paris-Saclay ;Fil: Michel, Patrick Pierre. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; FranciaMDPI2023-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/233552Tourville, Aurore; Viguier, Sarah; González Lizarraga, Maria Florencia; Tomas Grau, Rodrigo Hernán; Ramirez, Paola; et al.; Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives; MDPI; Antioxidants; 12; 3; 2-2023; 1-232076-3921CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/2076-3921/12/3/575info:eu-repo/semantics/altIdentifier/doi/10.3390/antiox12030575info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:19:04Zoai:ri.conicet.gov.ar:11336/233552instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:19:05.132CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives
title Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives
spellingShingle Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives
Tourville, Aurore
DOPAMINE NEURONS
PARKINSON'S DISEASE
FERROPTOSIS
TETRACYCLINES
title_short Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives
title_full Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives
title_fullStr Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives
title_full_unstemmed Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives
title_sort Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives
dc.creator.none.fl_str_mv Tourville, Aurore
Viguier, Sarah
González Lizarraga, Maria Florencia
Tomas Grau, Rodrigo Hernán
Ramirez, Paola
Brunel, Jean Michel
Dos Santos Pereira, Mauricio
Del Bel, Elaine
Chehin, Rosana Nieves
Ferrié, Laurent
Raisman Vozari, Rita
Figadère, Bruno
Michel, Patrick Pierre
author Tourville, Aurore
author_facet Tourville, Aurore
Viguier, Sarah
González Lizarraga, Maria Florencia
Tomas Grau, Rodrigo Hernán
Ramirez, Paola
Brunel, Jean Michel
Dos Santos Pereira, Mauricio
Del Bel, Elaine
Chehin, Rosana Nieves
Ferrié, Laurent
Raisman Vozari, Rita
Figadère, Bruno
Michel, Patrick Pierre
author_role author
author2 Viguier, Sarah
González Lizarraga, Maria Florencia
Tomas Grau, Rodrigo Hernán
Ramirez, Paola
Brunel, Jean Michel
Dos Santos Pereira, Mauricio
Del Bel, Elaine
Chehin, Rosana Nieves
Ferrié, Laurent
Raisman Vozari, Rita
Figadère, Bruno
Michel, Patrick Pierre
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv DOPAMINE NEURONS
PARKINSON'S DISEASE
FERROPTOSIS
TETRACYCLINES
topic DOPAMINE NEURONS
PARKINSON'S DISEASE
FERROPTOSIS
TETRACYCLINES
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Several studies have reported that the tetracycline (TC) class antibiotic doxycycline (DOX) is effective against Parkinson?s disease (PD) pathomechanisms. The aim of the present work was three-fold: (i) Establish a model system to better characterize neuroprotection by DOX; (ii) Compare the rescue effect of DOX to that of other TC antibiotics; (iii) Discover novel neuroprotective TCs having reduced antibiotic activity. For that, we used cultures of mouse midbrain dopamine (DA) neurons and experimental conditions that model iron-mediated oxidative damage, a key mechanism in PD pathobiology. We found that DOX and the other TC antibiotic, demeclocycline (DMC), provided sustained protection to DA neurons enduring iron-mediated insults, whereas chlortetracycline and non-TC class antibiotics did not. Most interestingly, non-antibiotic derivatives of DOX and DMC, i.e., DDOX and DDMC, respectively, were also robustly protective for DA neurons. Interestingly, DOX, DDOX, DMC, and DDMC remained protective for DA neurons until advanced stages of neurodegeneration, and the rescue effects of TCs were observable regardless of the degree of maturity of midbrain cultures. Live imaging studies with the fluorogenic probes DHR-123 and TMRM revealed that protective TCs operated by preventing intracellular oxidative stress and mitochondrial membrane depolarization, i.e., cellular perturbations occurring in this model system as the ultimate consequence of ferroptosis-mediated lipid peroxidation. If oxidative/mitochondrial insults were generated acutely, DOX, DDOX, DMC, and DDMC were no longer neuroprotective, suggesting that these compounds are mostly effective when neuronal damage is chronic and of low-intensity. Overall, our data suggest that TC derivatives, particularly those lacking antibiotic activity, might be of potential therapeutic utility to combat low-level oxidative insults that develop chronically in the course of PD neurodegeneration.
Fil: Tourville, Aurore. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
Fil: Viguier, Sarah. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
Fil: González Lizarraga, Maria Florencia. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Tomas Grau, Rodrigo Hernán. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Ramirez, Paola. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
Fil: Brunel, Jean Michel. Universite Paris-Saclay ;
Fil: Dos Santos Pereira, Mauricio. No especifíca;
Fil: Del Bel, Elaine. No especifíca;
Fil: Chehin, Rosana Nieves. Universidad Nacional de Tucumán. Instituto de Investigaciones En Medicina Molecular y Celular Aplicada del Bicentenario. - Gobierno de la Provincia de Tucumán. Ministerio de Salud. Sistema Provincial de Salud. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet Noa Sur. Instituto de Investigaciones en Medicina Molecular y Celular Aplicada del Bicentenario; Argentina
Fil: Ferrié, Laurent. Universite Paris-Saclay ;
Fil: Raisman Vozari, Rita. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
Fil: Figadère, Bruno. Universite Paris-Saclay ;
Fil: Michel, Patrick Pierre. Centre de Recherche de I'Institut du Cerveau et de la Moelle Epinière; Francia
description Several studies have reported that the tetracycline (TC) class antibiotic doxycycline (DOX) is effective against Parkinson?s disease (PD) pathomechanisms. The aim of the present work was three-fold: (i) Establish a model system to better characterize neuroprotection by DOX; (ii) Compare the rescue effect of DOX to that of other TC antibiotics; (iii) Discover novel neuroprotective TCs having reduced antibiotic activity. For that, we used cultures of mouse midbrain dopamine (DA) neurons and experimental conditions that model iron-mediated oxidative damage, a key mechanism in PD pathobiology. We found that DOX and the other TC antibiotic, demeclocycline (DMC), provided sustained protection to DA neurons enduring iron-mediated insults, whereas chlortetracycline and non-TC class antibiotics did not. Most interestingly, non-antibiotic derivatives of DOX and DMC, i.e., DDOX and DDMC, respectively, were also robustly protective for DA neurons. Interestingly, DOX, DDOX, DMC, and DDMC remained protective for DA neurons until advanced stages of neurodegeneration, and the rescue effects of TCs were observable regardless of the degree of maturity of midbrain cultures. Live imaging studies with the fluorogenic probes DHR-123 and TMRM revealed that protective TCs operated by preventing intracellular oxidative stress and mitochondrial membrane depolarization, i.e., cellular perturbations occurring in this model system as the ultimate consequence of ferroptosis-mediated lipid peroxidation. If oxidative/mitochondrial insults were generated acutely, DOX, DDOX, DMC, and DDMC were no longer neuroprotective, suggesting that these compounds are mostly effective when neuronal damage is chronic and of low-intensity. Overall, our data suggest that TC derivatives, particularly those lacking antibiotic activity, might be of potential therapeutic utility to combat low-level oxidative insults that develop chronically in the course of PD neurodegeneration.
publishDate 2023
dc.date.none.fl_str_mv 2023-02
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 http://hdl.handle.net/11336/233552
Tourville, Aurore; Viguier, Sarah; González Lizarraga, Maria Florencia; Tomas Grau, Rodrigo Hernán; Ramirez, Paola; et al.; Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives; MDPI; Antioxidants; 12; 3; 2-2023; 1-23
2076-3921
CONICET Digital
CONICET
url http://hdl.handle.net/11336/233552
identifier_str_mv Tourville, Aurore; Viguier, Sarah; González Lizarraga, Maria Florencia; Tomas Grau, Rodrigo Hernán; Ramirez, Paola; et al.; Rescue of Dopamine Neurons from Iron-Dependent Ferroptosis by Doxycycline and Demeclocycline and Their Non-Antibiotic Derivatives; MDPI; Antioxidants; 12; 3; 2-2023; 1-23
2076-3921
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/2076-3921/12/3/575
info:eu-repo/semantics/altIdentifier/doi/10.3390/antiox12030575
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
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dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
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reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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