Neuroprotection of active principles from Cudrania tricuspidata by the induction of autophagy with mTOR inhibition in rotenone-induced Parkinsons disease model

Abstract

Parkinsons disease (PD) is characterized by severe motor deficits, cogwheel rigidity, bradykinesia, and the loss of dopaminergic neurons. The etiology of PD has not been clearly identified

However, the final common pathway in PD pathogenesis leads to the excessive deposition of toxins and to misfolding of proteins such as α-synuclein, and failure to degrade impaired protein might lead to the neuronal cell death associated with PD. Autophagy is a self-degradative process that removes aggregated proteins, damaged organelles, and intracellular pathogens. Recent studies have demonstrated dysregulation of the autophagy pathway in the brains of PD patients and in animal models of PD, suggesting a pivotal role for autophagy in the pathogenesis of PD. Rotenone, a common pesticide and inhibitor of mitochondrial complex I, induces loss of dopaminergic neurons and consequential aspects of PD. In this study, the effects of natural products on rotenone-mediated signaling in SH-SY5Y neuroblastoma cell were investigated to discover new lead compounds for the treatment of PD.

Cudrania tricuspidata (Moraceae) is a subtropical tree that is widely distributed in Korea, China, and Japan. The fruits of C. tricuspidata are used in jams, juices, and a fermented alcoholic beverage with sugar, and they are commercially produced as food in Korea. Also, the cortex and rood bark of C. tricuspidata have been used as a traditional medicine for inflammation and tumors. A recent study demonstrated that the extracts of C. tricuspidata protect neurons against oxidative stress-induced cytotoxicity and have inhibitory effects on nitric oxide synthase (NOS). The compounds isolated from C. tricuspidata are primarily xanthones and flavones in addition to some alkaloids, lignins, coumarins, polysaccharides, and chromones. The xanthones from the root bark of C. tricuspidata have been reported to exert protective effects against 6-OHDA-induced neurotoxicity.

In this study, the effects of active compounds from the C. tricuspidata extracts on inducing autophagy were studied. Gerontoxanthone C (GXC) isolated from the root barks of the C. tricuspidata protected against rotenone-induced neuronal cell death and the collapse of mitochondrial membrane potential (MMP) through induction autophagy with mTOR inhibition in SH-SY5Y cells. Based on the results, it was suggested that GXC might be promising candidates for the therapy of familiar PD via facilitating recovery of damaged organelles.

Key words: Parkinsons disease, PD, neuroprotection, autophagy, mTOR, Cudrania tricuspidata

Student Number : 2016-29887