Abstract
The movement disorder Parkinson’s disease (PD) is the second most frequently diagnosed neurodegenerative disease, and is associated with aging, the environment, and genetic factors. The intracellular aggregation of α-synuclein and the loss of dopaminergic neurons in the substantia nigra pars compacta are the pathological hallmark of PD. At present, there is no successful treatment for PD. Maackiain (MK) is a flavonoid extracted from dried roots of Sophora flavescens Aiton. MK has emerged as a novel agent for PD treatment that acts by inhibiting monoamine oxidase B. In this study, we assessed the neuroprotective potential of MK in Caenorhabditis elegans and investigated possible mechanism of this neuroprotection in the human SH-SY5Y cell line. We found that MK significantly reduced dopaminergic neuron damage in 6-hydroxydopamine (6-OHDA)-exposed worms of the BZ555 strain, with corresponding improvements in food-sensing behavior and life-span. In transgenic worms of strain NL5901 treated with 0.25 mM MK, the accumulation of α-synuclein was diminished by 27% (p < 0.01) compared with that in untreated worms. Moreover, in worms and the SH-SY5Y cell line, we confirmed that the mechanism of MK-mediated protection against PD pathology may include blocking apoptosis, enhancing the ubiquitin-proteasome system, and augmenting autophagy by increasing PINK1/parkin expression. The use of small interfering RNA to downregulate parkin expression in vivo and in vitro could reverse the benefits of MK in PD models. MK may have considerable therapeutic applications in PD.
Highlights
Parkinson’s disease (PD) is an aging-associated neurodegenerative movement disorder that is characterized by the progressive aggregation of α-synuclein in surviving neurons and the selective death of dopaminergic neurons in the substantia nigra pars compacta [1]
We used pharmacologic and transgenic C. elegans models to confirm that treatment with MK can ameliorate the degeneration of dopaminergic neurons induced by 6-OHDA, recovering the food-sensing behavior and life-span of worms as well as improving human α-synuclein protein accumulation in a dose-dependent manner
The neuroprotective roles of MK in 6-OHDA-induced dopaminergic neuron degeneration model of C. elegans may be related to its antioxidant, and anti-apoptotic activity
Summary
Parkinson’s disease (PD) is an aging-associated neurodegenerative movement disorder that is characterized by the progressive aggregation of α-synuclein in surviving neurons (named Lewy bodies) and the selective death of dopaminergic neurons in the substantia nigra pars compacta [1]. Symptoms include tremor at rest, rigidity, and slowed movements [2]. Studies show that by 2020, approximately 930,000 people in the United States will have the disease, and by 2030 the incidence is predicted to increase to 1.2 million [3]. The movement of α-synuclein from the gut to the brain has been proposed to be pathogenic [5], and some studies have shown that gut microbes are associated with the regulation of motor deficits in PD models [6]. There is no successful pharmacologic treatment for curing PD
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