Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism

Glial cell line-derived neurotrophic factor (GDNF) has been investigated as a therapeutic agent for Parkinson's disease (PD), albeit with variable clinical outcomes. In the brain, GDNF is predominantly produced by striatal interneurons. Given that Gdnf gene expression is regulated by cyclic ade...

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Autores: d’Anglemont de Tassigny, Xavier, Jiménez-Medina, Alejandro, López-López, Ivette, López-Barneo, José
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/412618
Acceso en línea:http://hdl.handle.net/10261/412618
Access Level:acceso abierto
Palabra clave:Ibudilast
Neuroprotection
Phosphodiesterase inhibitors
Preclinical chronic parkinsonism
Striatal GDNF modulation
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spelling Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonismd’Anglemont de Tassigny, XavierJiménez-Medina, AlejandroLópez-López, IvetteLópez-Barneo, JoséIbudilastNeuroprotectionPhosphodiesterase inhibitorsPreclinical chronic parkinsonismStriatal GDNF modulationGlial cell line-derived neurotrophic factor (GDNF) has been investigated as a therapeutic agent for Parkinson's disease (PD), albeit with variable clinical outcomes. In the brain, GDNF is predominantly produced by striatal interneurons. Given that Gdnf gene expression is regulated by cyclic adenosine monophosphate (cAMP)-dependent signaling, a compelling strategy for PD treatment is the pharmacological elevation of intracellular cAMP. This approach aims to enhance endogenous GDNF, offering potential neuroprotective benefits. In this study, we show that selective inhibition of phosphodiesterases (PDEs) subtypes, therefore enhancing intracellular cAMP levels, increases Gdnf mRNA expression in striatal slices ex vivo; however, achieving this effect in vivo proved more challenging. To address this, we evaluated Ibudilast, a clinically approved non-selective PDE inhibitor. Ibudilast robustly upregulated striatal Gdnf expression both ex vivo and in vivo following systemic administration. In a chronic MPTP mouse model of PD, Ibudilast treatment conferred significant neuroprotection, as evidenced by preservation of tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra, attenuation of TH+ fiber loss in the striatum, and mitigation of striatal dopamine depletion. Given its established clinical use and favorable safety profile, these findings support further investigation of Ibudilast as a potential disease-modifying therapy in PD.This study was supported by Fundación Tatiana Pérez de Guzmán el Bueno Foundation, Spanish Ministry of Science, Innovation and Universities (PID2022-138131OB-I00, PREP2022-000587), and Andalusian Plan for Research, Development and Innovation (P18-RT-3100).We appreciate support from the “Tatiana Pérez de Guzman el Bueno Foundation,” the Andalusian Plan for Research, Development and Innovation (PAIDI2020, project P18-RT-3100), and the Spanish Ministry of Science, Innovation and Universities (projects PID2022-138131OB-I00, PREP2022-000587, and PID2022-136685OA-I00). We are grateful to the mass spectrometry core facility (Citius) and Dr. Martiniano Santiago Pavon (Dept. of Pharmacy, University of Seville) for consultation and special reagent supply.Peer reviewedWiley-VCHInternational Society for NeurochemistryFundación Tatiana Pérez de Guzmán el BuenoAgencia Estatal de Investigación (España)Ministerio de Ciencia, Innovación y Universidades (España)Junta de AndalucíaLópez-Barneo, José [0000-0003-4101-6095]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/412618reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-138131OB-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136685OA-I00The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1111/jnc.70321https://doi.org/10.1111/jnc.70321Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4126182026-05-22T06:33:51Z
dc.title.none.fl_str_mv Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism
title Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism
spellingShingle Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism
d’Anglemont de Tassigny, Xavier
Ibudilast
Neuroprotection
Phosphodiesterase inhibitors
Preclinical chronic parkinsonism
Striatal GDNF modulation
title_short Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism
title_full Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism
title_fullStr Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism
title_full_unstemmed Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism
title_sort Phosphodiesterase Inhibition Increases Striatal GDNF and Protects Against Preclinical Parkinsonism
dc.creator.none.fl_str_mv d’Anglemont de Tassigny, Xavier
Jiménez-Medina, Alejandro
López-López, Ivette
López-Barneo, José
author d’Anglemont de Tassigny, Xavier
author_facet d’Anglemont de Tassigny, Xavier
Jiménez-Medina, Alejandro
López-López, Ivette
López-Barneo, José
author_role author
author2 Jiménez-Medina, Alejandro
López-López, Ivette
López-Barneo, José
author2_role author
author
author
dc.contributor.none.fl_str_mv Fundación Tatiana Pérez de Guzmán el Bueno
Agencia Estatal de Investigación (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Junta de Andalucía
López-Barneo, José [0000-0003-4101-6095]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Ibudilast
Neuroprotection
Phosphodiesterase inhibitors
Preclinical chronic parkinsonism
Striatal GDNF modulation
topic Ibudilast
Neuroprotection
Phosphodiesterase inhibitors
Preclinical chronic parkinsonism
Striatal GDNF modulation
description Glial cell line-derived neurotrophic factor (GDNF) has been investigated as a therapeutic agent for Parkinson's disease (PD), albeit with variable clinical outcomes. In the brain, GDNF is predominantly produced by striatal interneurons. Given that Gdnf gene expression is regulated by cyclic adenosine monophosphate (cAMP)-dependent signaling, a compelling strategy for PD treatment is the pharmacological elevation of intracellular cAMP. This approach aims to enhance endogenous GDNF, offering potential neuroprotective benefits. In this study, we show that selective inhibition of phosphodiesterases (PDEs) subtypes, therefore enhancing intracellular cAMP levels, increases Gdnf mRNA expression in striatal slices ex vivo; however, achieving this effect in vivo proved more challenging. To address this, we evaluated Ibudilast, a clinically approved non-selective PDE inhibitor. Ibudilast robustly upregulated striatal Gdnf expression both ex vivo and in vivo following systemic administration. In a chronic MPTP mouse model of PD, Ibudilast treatment conferred significant neuroprotection, as evidenced by preservation of tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra, attenuation of TH+ fiber loss in the striatum, and mitigation of striatal dopamine depletion. Given its established clinical use and favorable safety profile, these findings support further investigation of Ibudilast as a potential disease-modifying therapy in PD.
publishDate 2025
dc.date.none.fl_str_mv 2025
2026
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/412618
url http://hdl.handle.net/10261/412618
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#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-138131OB-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136685OA-I00
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1111/jnc.70321
https://doi.org/10.1111/jnc.70321
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley-VCH
International Society for Neurochemistry
publisher.none.fl_str_mv Wiley-VCH
International Society for Neurochemistry
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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