{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T06:14:01Z","timestamp":1781590441473,"version":"3.54.5"},"reference-count":53,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Glial cell line\u2010derived 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\n                    <jats:italic>Gdnf<\/jats:italic>\n                    gene expression is regulated by cyclic adenosine monophosphate (cAMP)\u2010dependent 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\n                    <jats:italic>Gdnf<\/jats:italic>\n                    mRNA expression in striatal slices ex\u00a0vivo; however, achieving this effect in\u00a0vivo proved more challenging. To address this, we evaluated Ibudilast, a clinically approved non\u2010selective PDE inhibitor. Ibudilast robustly upregulated striatal\n                    <jats:italic>Gdnf<\/jats:italic>\n                    expression both ex\u00a0vivo and in\u00a0vivo following systemic administration. In a chronic MPTP mouse model of PD, Ibudilast treatment conferred significant neuroprotection, as evidenced by preservation of tyrosine hydroxylase\u2010positive (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\u2010modifying therapy in PD.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70321-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70321","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T05:20:54Z","timestamp":1765516854000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Phosphodiesterase Inhibition Increases Striatal\n                    <scp>GDNF<\/scp>\n                    and Protects Against Preclinical Parkinsonism"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5346-1156","authenticated-orcid":false,"given":"Xavier","family":"d\u2019Anglemont de Tassigny","sequence":"first","affiliation":[{"name":"Institute of Biomedicine of Seville (IBiS) University Hospital \u201cVirgen del Roc\u00edo\u201d, CSIC, University of Seville  Seville Spain"},{"name":"Department of Medical Physiology and Biophysics University of Seville Medical School  Seville Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Jim\u00e9nez\u2010Medina","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of Seville (IBiS) University Hospital \u201cVirgen del Roc\u00edo\u201d, CSIC, University of Seville  Seville Spain"},{"name":"Department of Medical Physiology and Biophysics University of Seville Medical School  Seville Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivette","family":"L\u00f3pez\u2010L\u00f3pez","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of Seville (IBiS) University Hospital \u201cVirgen del Roc\u00edo\u201d, CSIC, University of Seville  Seville Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4101-6095","authenticated-orcid":false,"given":"Jos\u00e9","family":"L\u00f3pez\u2010Barneo","sequence":"additional","affiliation":[{"name":"Institute of Biomedicine of Seville (IBiS) University Hospital \u201cVirgen del Roc\u00edo\u201d, CSIC, University of Seville  Seville Spain"},{"name":"Department of Medical Physiology 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