Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson’s Disease

Abstract

The motor and nonmotor symptoms of Parkinson’s disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate β sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated β sheet aggregate (β23), and prevented β23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII’s neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation.

SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models

“…The level of the SGK1 inhibitor GSK‐650394 in the brains of PD mice was determined according to a previous report (Ham et al , 2019). Briefly, the brain tissues were collected 30 min after the last administration of GSK‐650394 at a dose of 3 mg/kg.…”

Brain Endothelial P-Glycoprotein Level Is Reduced in Parkinson’s Disease via a Vitamin D Receptor-Dependent Pathway

“…For stereotaxic injection of 6-OHDA (10 µg), 3-month-old C57BL/6N mice were anesthetized with alfaxan (60 mg/kg) on day 6. The 6-OHDA injection procedure was performed as described previously [ 38 ]. The combinatorial α-synucleinopathy PD model was generated by simultaneously injecting PFF (10 µg; ventral tegmental area: AP, −3.4 mm; ML, −0.5 mm; DV, −4.3 mm) and rAAV-αSyn (AAV serotype 1, 1 µL of titer 5 × 1011 GC/mL; substantia nigra pars compacta [SNpc]: AP, −3.4 mm; ML, −1.3 mm; DV, −4.3 mm) unilaterally.…”

“…After intracardial fixation of mice, we followed the previously reported procedure [ 38 ] for brain coronal sectioning, anti-TH immunohistochemistry, and unbiased stereological TH-positive cell counting. All stereological counting was performed with the counter blinded to each mouse treatment.…”

Neurobiology Research in Parkinson’s Disease

“…Disaggregation of alfa-synuclein might be an effective therapy for PD. Peucedanocoumarin III administration resulted in reduced dopaminergic neuronal loss in the 6-hydroxydopamine mice model of PD [3]. The demonstrated neuroprotective effects and safety of peucedanocoumarin III showed the possibility of the clinical application.…”