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 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.