NEUROPROTECTIVE EFFICACY OF THE PDE INHIBITOR IBUDILAST IN A CHRONIC MPTP MODEL OF PARKINSON’S DISEASE

Background: While glial cell line-derived neurotrophic factor (GDNF) is a potent survival factor for dopaminergic (DA) neurons, its clinical use in Parkinson’s disease (PD) is limited by delivery challenges. We previously demonstrated that cyclic adenosine monophosphate (cAMP)/CREB signaling pathway upregulates endogenous GDNF in parvalbumin interneurons of the striatum.
Methods: In this study, we have tested phosphodiesterase (PDE) inhibitors -which are small molecules that prevent cAMP and cGMP degradation- on GDNF synthesis ex vivo and in vivo. We investigated the neuroprotective potential of Ibudilast -a broad range PDE inhibitor- in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. Mice received systemic Ibudilast (5 or 10 mg/kg, i.p.) administered 4–5 hours prior to MPTP exposure. Neurodegeneration was quantified via tyrosine hydroxylase-positive (TH+) neuron counts in the substantia nigra pars compacta (SNpc), TH+ fiber density in the striatum, and striatal dopamine (DA) levels via HPLC.
Results: Our findings indicate that selective and broader range PDE inhibitors stimulate striatal GDNF synthesis. Importantly, Ibudilast treatment provides significant neuroprotection, mitigating MPTP-induced loss of DA cell bodies, axonal projections and striatal dopamine content. This is likely -but not only- driven by the rapid induction of striatal GDNF within the treatment window.
Conclusions: Given its established safety profile and existing regulatory approval for other conditions, Ibudilast represents a promising disease-modifying candidate for early-stage PD. Ongoing studies are currently evaluating its efficacy in a post-insult paradigm to better reflect the clinical reality of PD diagnosis and treatment.