Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Kwadwo Ofori
,
Anurupa Ghosh
ORCID logo ,
Dinesh Kumar Verma
,
Darice Wheeler
,
Gabriela N Cabrera
,
Jong-Bok Seo
,
Yong-Hwan Kim
* ORCID logo
Version 1 : Received: 16 August 2023 / Approved: 17 August 2023 / Online: 18 August 2023 (10:55:57 CEST)

A peer-reviewed article of this Preprint also exists.

Ofori, K.; Ghosh, A.; Verma, D.K.; Wheeler, D.; Cabrera, G.; Seo, J.-B.; Kim, Y.-H. A Novel NOX Inhibitor Alleviates Parkinson’s Disease Pathology in PFF-Injected Mice. Int. J. Mol. Sci. 2023, 24, 14278. Ofori, K.; Ghosh, A.; Verma, D.K.; Wheeler, D.; Cabrera, G.; Seo, J.-B.; Kim, Y.-H. A Novel NOX Inhibitor Alleviates Parkinson’s Disease Pathology in PFF-Injected Mice. Int. J. Mol. Sci. 2023, 24, 14278.

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 10nM. 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 SNc contributed to neuroprotective/recovery effects, making it a potential therapeutic option for PD.

Keywords

α-Synuclein preformed fibrils (PFF); cytotoxicity; Reactive Oxygen Species (ROS); oxidative stress; and protein aggregation

Subject

Biology and Life Sciences, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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