n-Butylidenephthalide Protects against Dopaminergic Neuron Degeneration and α-Synuclein Accumulation in Caenorhabditis elegans Models of Parkinson's Disease

Abstract

BackgroundParkinson's disease (PD) is the second most common degenerative disorder of the central nervous system that impairs motor skills and cognitive function. To date, the disease has no effective therapies. The identification of new drugs that provide benefit in arresting the decline seen in PD patients is the focus of much recent study. However, the lengthy time frame for the progression of neurodegeneration in PD increases both the time and cost of examining potential therapeutic compounds in mammalian models. An alternative is to first evaluate the efficacy of compounds in Caenorhabditis elegans models, which reduces examination time from months to days. n-Butylidenephthalide is the naturally-occurring component derived from the chloroform extract of Angelica sinensis. It has been shown to have anti-tumor and anti-inflammatory properties, but no reports have yet described the effects of n-butylidenephthalide on PD. The aim of this study was to assess the potential for n-butylidenephthalide to improve PD in C. elegans models.Methodology/Principal FindingsIn the current study, we employed a pharmacological strain that expresses green fluorescent protein specifically in dopaminergic neurons (BZ555) and a transgenic strain that expresses human α-synuclein in muscle cells (OW13) to investigate the antiparkinsonian activities of n-butylidenephthalide. Our results demonstrate that in PD animal models, n-butylidenephthalide significantly attenuates dopaminergic neuron degeneration induced by 6-hydroxydopamine; reduces α-synuclein accumulation; recovers lipid content, food-sensing behavior, and dopamine levels; and prolongs life-span of 6-hydroxydopamine treatment, thus revealing its potential as a possible antiparkinsonian drug. n-Butylidenephthalide may exert its effects by blocking egl-1 expression to inhibit apoptosis pathways and by raising rpn-6 expression to enhance the activity of proteasomes.Conclusions/Significance n-Butylidenephthalide may be one of the effective neuroprotective agents for PD.

Lack of effect of Z-butylidenephthalide on presynaptic N-type Ca2+ channels in isolated guinea-pig ileum

“…Consistently, Z-Bdph has been reported to have an anti-hyperglycemic effect in mice (Brindis et al 2011). Recently, Z-Bdph has been reported to have a protective effect against Parkinson's disease (Fu et al 2014). Z-Bdph was reported to reverse the deficits of inhibitory avoidance performance and improves memory in rats (Hsieh et al 2001).…”

N-butylidenephthalide Attenuates Alzheimer's Disease-Like Cytopathy in Down Syndrome Induced Pluripotent Stem Cell-Derived Neurons

“…Bdph has also been reported to improve dopaminergic neuron degeneration and α-synuclein accumulation in Caenorhabditis elegans models of Parkinson's disease32, though the underlying mechanism is still unclear. Notably, n-butylphthalide (NBP), which shares the same chemical structure as Bdph, shows strong neuron protection activity in acute brain ischemia and neural degenerative diseases3334353637.…”

Astragalus Polysaccharide Suppresses 6‐Hydroxydopamine‐Induced Neurotoxicity in Caenorhabditis elegans

“…6-OHDA (Sigma, St. Louis, MO, USA) was used to induce selective degeneration of dopaminergic neurons in BZ555 nematodes as described previously [16]. Briefly, synchronized L3 larvae were incubated with 50 mM 6-OHDA and 10 mM ascorbic acid in S. medium supplemented with E .…”

“…The nematode dopaminergic neurodegeneration was examined as described previously [16]. In brief, after treatment with 6-OHDA and astragalan, the nematodes were washed with M9 buffer, paralyzed by 50 mM sodium azide, and then mounted onto a 2% agar pad on a glass slide.…”

“…The food-sensing behavior was carried out as described [16]. Briefly, a 9 cm NGM agar plate was spread with E. coli OP50 overnight at 37°C in a ring with an inner diameter of 1 cm and an outer diameter of 8 cm.…”