Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson's Disease.
Heejeong KimHan-Joo MaengJi Hun KimJin-Ha YoonYohan OhSeung-Mann PaekByoung Dae LeePublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- mouse model
- white matter
- resting state
- spinal cord
- oxidative stress
- physical activity
- single cell
- binding protein
- high fat diet induced
- adipose tissue
- multiple sclerosis
- drug delivery
- skeletal muscle
- protein protein
- amyotrophic lateral sclerosis
- insulin resistance
- cancer therapy
- ultrasound guided
- small molecule
- brain injury