Abstract
Vasicinone is a quinazoline alkaloid isolated from the Adhatoda vasica plant. In this study, we explored the neuroprotective effect and underlying molecular mechanism of vasicinone against paraquat-induced cellular apoptosis in SH-SY5Y cells. Vasicinone reduced the paraquat-induced loss of cell viability, rescued terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic nuclei, and suppressed generation of reactive oxygen species (ROS) in a dose-dependent manner. Western blotting analysis revealed that vasicinone increased the phosphorylation of IGF1R/PI3K/AKT cell survival signaling molecules and downregulated the paraquat-induced, mitogen-activated protein kinase (MAPK)/c-Jun N-terminal kinase (JNK)-mediated apoptotic pathways compared to that observed in cells not treated with vasicinone. This protection depended critically on the activation of IGF1R, and the silencing of IGF1R by siRNA completely abrogated the protective effect of vasicinone in SH-SY5Y cells. Our findings indicated that vasicinone is a potential candidate for the treatment of Parkinson’s disease and possibly other oxidative stress-related neurodegenerative disorders.
Highlights
Parkinson’s disease (PD) is the second most common age-dependent, chronic and progressive neurodegenerative disease and affects 2–3% of the population ≥65 years of age
We found that paraquat significantly reduced cell viability in a dose-dependent manner, and the cell survival rate was approximately 64% when the cells were treated with 300 μM of paraquat for 24 h compared to that observed for control cells
The mitogen-activated protein kinase (MAPK) signaling pathway is associated with progressive dysfunction in multiple neurodegenerative diseases and mitochondrial-mediated apoptosis; we investigated the protective effect of vasicinone on members of the paraquat-induced MAPK pathway including Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), c-JUN and p38 in SH-SY5Y cells
Summary
Parkinson’s disease (PD) is the second most common age-dependent, chronic and progressive neurodegenerative disease and affects 2–3% of the population ≥65 years of age. It is distinguished by the selective degeneration of dopamine-producing neurons in the substantia nigra pars compacta [1], causing striatal dopamine deficiency and intracellular α-synuclein aggregation (Lewy bodies), which are the neuropathological hallmarks of Parkinson’s disease. The accumulation of reactive oxygen species (ROS), mitochondrial membrane potential loss, adenosine triphosphate (ATP) depletion and the activation of the caspase cascade have been observed in the substantia nigra and cerebrospinal fluid of PD patients [5,6]
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