Elsevier

Redox Biology

Volume 22, April 2019, 101134
Redox Biology

Research Paper
Inhibition of NADPH oxidase by apocynin prevents learning and memory deficits in a mouse Parkinson's disease model

https://doi.org/10.1016/j.redox.2019.101134Get rights and content
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Abstract

The activation of NADPH oxidase contributes to dopaminergic neurodegeneration and motor deficits in Parkinson's disease (PD). However, whether NADPH oxidase is involved in non-motor symptoms, especially cognitive dysfunction in PD remains unknown. This study is undertaken to characterize the effects of inhibition of NADPH oxidase by a widely used NADPH oxidase inhibitor apocynin on learning and memory deficits in paraquat and maneb-induced mouse PD model. Results showed that mice injected with paraquat and maneb displayed impairments of spatial learning and memory, which was associated with reduced tyrosine hydroxylase expression as well as increased neurodegeneration, synaptic loss, α-synuclein expression and Ser129-phosphorylation in the hippocampus. Interestingly, apocynin treatment significantly ameliorated learning and memory deficits as well as hippocampal neurodegeneration and α-synuclein pathology in mice treated with these two pesticides. Mechanistically, we found that apocynin mitigated paraquat and maneb-induced NADPH oxidase activation and related oxidative stress. Furthermore, reduced microglial activation and M1 polarization were observed in apocynin and paraquat and maneb co-treated mice compared with paraquat and maneb alone group. Finally, apocynin inhibited the activation of signal transducers and activators of transcription 1 (STAT1) and nuclear factor kappa B (NF-κB) pathways, two key regulatory factors for microglial M1 inflammatory responses, in paraquat and maneb-treated mice. Altogether, our findings implied that NADPH oxidase mediates learning and memory deficits in PD, and inhibition of NADPH oxidase by apocynin blocks impairments of learning and memory via the suppression of oxidative stress and neuroinflammation.

Abbreviations

AD
Alzheimer disease
Iba-1
ionized calcium binding adaptor molecule-1
iNOS
inducible nitric oxide synthase
LPS
lipopolysaccharide
MDA
malondialdehyde
MPO
myeloperoxidase
MWM
morris maze test
NF-κB
nuclear factor-κB
PD
Parkinson's disease
P + M
paraquat and maneb
ROS
reactive oxygen species
SNpc
substantia nigra pars compacta
SOD
superoxide dismutase
STAT1
signal transducers and activators of transcription 1
TH
tyrosine hydroxylase
TNFα
tumor necrosis factor α

Keywords

Parkinson's disease
Nonmotor symptoms
Cognitive deficits
NADPH oxidase
Neuroinflammation

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1

These authors contributed equally to this work.