Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 8, Pages -Publisher
MDPI
DOI: 10.3390/ijms23084262
Keywords
alpha-synuclein preformed fibrils; ROS inhibition; Thioflavin T; oxidative stress; protein aggregation
Funding
- AptaBio Therapeutics Inc. [F7097]
- NIH-R15 [1R15NS121784]
- Delaware Neuroscience Center [NIH-5P20GM103653]
- DE-INBRE [NIH-P20GM103446]
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This study evaluated the efficacy of a novel NOX inhibitor in Parkinson's disease (PD) models, and found that the compound improved cell viability, reduced ROS levels, and decreased protein aggregation. Both mouse models treated with the compound showed alleviated motor deficits and reduced protein aggregation.
Parkinson's disease (PD) is a progressive neurodegenerative motor disorder without an available therapeutic to halt the formation of Lewy bodies for preventing dopaminergic neuronal loss in the nigrostriatal pathway. Since oxidative-stress-mediated damage has been commonly reported as one of the main pathological mechanisms in PD, we assessed the efficacy of a novel NOX inhibitor from AptaBio Therapeutics (C-6) in dopaminergic cells and PD mouse models. The compound reduced the cytotoxicity and enhanced the cell viability at various concentrations against MPP+ and alpha-synuclein preformed fibrils (PFFs). Further, the levels of ROS and protein aggregation were significantly reduced at the optimal concentration (1 mu M). Using two different mouse models, we gavaged C-6 at two different doses to the PD sign-displaying transgenic mice for 2 weeks and stereotaxically PFF-injected mice for 5 weeks. Our results demonstrated that both C-6-treated mouse models showed alleviated motor deficits in pole test, hindlimb clasping, crossbeam, rotarod, grooming, and nesting analyses. We also confirmed that the compound treatment reduced the levels of protein aggregation, along with phosphorylated-alpha-synuclein, in the striatum and ventral midbrain and further dopaminergic neuronal loss. Taken together, our results strongly suggest that NOX inhibition can be a potential therapeutic target for PD.
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