Synthetic Peucedanocoumarin IV Prevents alpha-Synuclein Neurotoxicity in an Animal Model of Parkinson's Disease

Abstract

Pathological protein inclusion formation and propagation are the main causes of neuronal dysfunction in diverse neurodegenerative diseases; therefore, current disease-modifying therapeutic strategies have targeted this disease protein aggregation process. Recently, we reported that peucedanocoumarin III (PCiii) is a promising therapeutic compound with the ability to disaggregate alpha-synuclein inclusion and protect dopaminergic neurons in Parkinson's disease (PD). Here, we found that trans-4 '-acetyl-3 '-tigloylkhellactone (racemic peucedanocoumarin IV [PCiv]), a structural isomer of PCiii with a higher synthetic yield presented a strong anti-aggregate activity to a degree comparable to that of PCiii. PCiv retained effective inhibitory function against beta-sheet aggregate-mimic beta 23 cytotoxicities and potently prevented alpha-synucleinopathy in alpha-synuclein preformed fibril (PFF)-treated mice cortical neurons. In detailed pharmacokinetic profiling of PCiv, oral administration of PCiv in rats exhibited an approximately 97-min half-life and 10% bioavailability. Moreover, tissue distribution analysis revealed favorable profiles of brain penetration with a 6.4 brain-to-plasma concentration ratio. The therapeutic efficacy of PCiv was further evaluated in a sporadic PD mouse model with a combinatorial co-injection of alpha-synuclein preformed fibril and recombinant adeno-associated virus expressing alpha-synuclein. Motor dysfunctions induced in this combinatorial alpha-synucleinopathy PD mouse model was almost completely rescued by PCiv diet administration, and this therapeutic effect is consistent with the marked prevention of dopaminergic neuron loss and suppression of alpha-synuclein aggregation. Taken together, our translational study suggests that PCiv is advantageous as a therapeutic agent for neurodegenerative diseases, especially with its good synthetic yield, high brain distribution, and anti-aggregate activity. PCiv may be useful in the management of alpha-synuclein inclusion formation and propagation at different stages of PD.