A Novel NOX Inhibitor Alleviates Parkinson’s Disease Pathology in PFF-Injected Mice

Kwadwo Ofori, Anurupa Ghosh, Dinesh Kumar Verma, Darice Wheeler, Gabriela Cabrera, Jong Bok Seo, Yong Hwan Kim

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Abstract

Oxidative stress-mediated damage is often a downstream result of Parkinson’s disease (PD), which is marked by sharp decline in dopaminergic neurons within the nigrostriatal regions of the brain, accounting for the symptomatic motor deficits in patients. Regulating the level of oxidative stress may present a beneficial approach in preventing PD pathology. Here, we assessed the efficacy of a nicotinamide adenine phosphate (NADPH) oxidase (NOX) inhibitor, an exogenous reactive oxygen species (ROS) regulator synthesized by Aptabio therapeutics with the specificity to NOX-1, 2 and 4. Utilizing N27 rat dopaminergic cells and C57Bl/6 mice, we confirmed that the exposures of alpha-synuclein preformed fibrils (PFF) induced protein aggregation, a hallmark in PD pathology. In vitro assessment of the novel compound revealed an increase in cell viability and decreases in cytotoxicity, ROS, and protein aggregation (Thioflavin-T stain) against PFF exposure at the optimal concentration of 10 nM. Concomitantly, the oral treatment alleviated motor-deficits in behavioral tests, such as hindlimb clasping, rotarod, pole, nesting and grooming test, via reducing protein aggregation, based on rescued dopaminergic neuronal loss. The suppression of NOX-1, 2 and 4 within the striatum and ventral midbrain regions including Substantia Nigra compacta (SNc) contributed to neuroprotective/recovery effects, making it a potential therapeutic option for PD.

Original languageEnglish
Article number14278
JournalInternational Journal of Molecular Sciences
Volume24
Issue number18
DOIs
StatePublished - Sep 2023

Keywords

  • cytotoxicity
  • oxidative stress
  • protein aggregation
  • reactive oxygen species (ROS)
  • α-synuclein preformed fibrils (PFF)

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