Neurotherapeutic effects of Vutiglabridin as a Paraoxonase-2 modulator in preclinical models of Parkinson’s disease

Background: Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease characterized by motor impairment resulting from the degeneration of dopaminergic neurons in the substantia nigra, alongside α -synuclein (α-syn) accumulation, mitochondrial dysfunction, and oxidative stress. Recent studies on PD treatment have focused primarily on exploring oxidative stress and mitochondrial function as ways to restore dopamine release. Notably, previous studies have demonstrated that Paraoxonase 2 (PON2) plays a critical role in neuroprotection and neuroinflammation by reducing oxidative stress in striatal neurons and astrocytes. Methods: In this study, we investigated the potential therapeutic effect of a newly developed drug, Vutiglabridin, which is demonstrated to augment the activity of PON2 in the mouse model of PD. We assessed the impact of Vutiglabridin in a PD model induced by MPP⁺ treatment and overexpression of the A53T mutated α-syn. Furthermore, we administered Vutiglabridin subsequent to PON2 gene knockdown through PON2-shRNA overexpression to elucidate the interplay between PON2 and Vutiglabridin. Result: Vutiglabridin effectively crosses the blood-brain barrier (BBB) and maintains a presence in the brain for over 24 h, achieving concentrations up to 2.5 times higher than in the bloodstream. It successfully binds to PON2 in both its (R) and (S) forms. Vutiglabridin reversed mitochondrial dysfunction, reduced oxidative stress, improved motor functions, and protected dopaminergic neurons against MPP+-induced damage. Similarly, in α-syn A53T overexpressed PD models, it not only reduced astrocytic reactivity and microglia activation but also doubled the tyrosine hydroxylase positive neurons /dopa decarboxylase positive neurons (TH+/DDC+) ratio, signifying enhanced neuronal health. However, these positive outcomes were absent in PON2-knockdown mice, underscoring Vutiglabridin’s reliance on PON2 for its neuroprotective effects. Conclusion: These findings indicate that Vutiglabridin may serve as a promising therapeutic approach for reducing reactive oxygen species (ROS) levels by modulating PON2 activity in Parkinson’s diseases.