Synthetic Peucedanocoumarin IV Prevents α-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 α-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 β-sheet aggregate-mimic β23 cytotoxicities and potently prevented α-synucleinopathy in α-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 α-synuclein preformed fibril and recombinant adeno-associated virus expressing α-synuclein. Motor dysfunctions induced in this combinatorial α-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 α-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 α-synuclein inclusion formation and propagation at different stages of PD.

Are Therapies That Target α-Synuclein Effective at Halting Parkinson’s Disease Progression? A Systematic Review

“…Inhibiting α-syn aggregation is an attractive target for combating α-syn-induced PD, and several groups have focused on the disaggregation of α-syn as a therapeutic mechanism [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], and these have been summarized and placed in ascending year of publication in Table 3 .…”

“…Studies were further divided into viral and non-viral methods of delivery. Studies that explored inhibition of the aggregation of α-syn ( n = 10) used a range of interventions, including aggregation inhibitors, targeted degradation and clearance, and molecular tweezer inhibitors [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ].…”

“…The administration of the small molecule trans -4′-acetyl-3′-tigloylkhellactone (racemic peucedanocoumarin IV (PCiv)) provided an agent able to suppress α-syn aggregation ( p < 0.01) and partially restore dopaminergic neuron loss ( p < 0.001) and motor function in a transgenic model of PD [ 61 ].…”

“…Inhibiting α-syn aggregation is an attractive target for combating the toxic aggregates that induce PD, and studies have focused on targeting thevaggregated forms of α-syn and/or promoting α-syn disaggregation [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ].…”

Syntheses, reactivity, and biological applications of coumarins

“…The inhibition of α-syn aggregation represents a promising disease-modifying strategy to halt or slow PD-related neurodegeneration ( De Luca et al, 2022 ). In 2022, Kim and others reported the prevention of α-synuclein aggregation activity and the neuroprotective effect of the synthetic coumarin derivative PCiv ( 182 ) ( Figure 1B ) ( Kim et al, 2022 ). This compound was able to inhibit α-syn aggregation in vitro and mitigated PFF-induced α-synucleinopathy in primary cortical neuron cultures.…”