Abstract
Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson’s disease (PD). Vasicinone is a quinazoline alkaloid from Adhatoda vasica. Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases α-synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting approximately 3.4% of the world’s population over 60 years of age [1,2]
Primary antibodies against SOD-1, SOD-2, GST, GPx, TOM-20, voltage-dependent anion channels (VDACs)-1, Parkin, PINK-1 and GAPDH were purchased from Santa Cruz Technology (Dallas, TX, USA), antibodies against DJ-1, α-synuclein, p-ULK, ATG7, ATG12 and LC3B were purchased from Cell
Results are shown as the mean ± standard deviation (SD). # p < 0.05, compared with control cells; * p < 0.05, compared with paraquat-treated cells
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting approximately 3.4% of the world’s population over 60 years of age [1,2] It is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain [3] and the aggregation of α-synuclein, which is a defining pathological characteristic of the disease [4]. Current therapies for PD are the administration of a dopamine precursor, anticholinergic agents, dopamine agonists, and levodopa (L-DOPA), which provide symptomatic relief for a few years [5,6] Their long-term usage is associated with a progressive decrease in drug response, motor fluctuations, dyskinesias, drug-associated toxicity and failure to prevent the progression of the disease [6]. We found that vasicinone significantly protect the SH-SY5Y cells from paraquat mediated toxicity, enhancing the clearance of misfolded proteins and defective mitochondria via autophagy
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