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Molecular Neurobiology

, Volume 56, Issue 4, pp 2653–2669 | Cite as

Loss of Brain Norepinephrine Elicits Neuroinflammation-Mediated Oxidative Injury and Selective Caudo-Rostral Neurodegeneration

  • Sheng Song
  • Lulu Jiang
  • Esteban A. Oyarzabal
  • Belinda Wilson
  • Zibo Li
  • Yen-Yu Ian Shih
  • Qingshan WangEmail author
  • Jau-Shyong HongEmail author
Article

Abstract

Environmental toxicant exposure has been strongly implicated in the pathogenesis of Parkinson’s disease (PD). Clinical manifestations of non-motor and motor symptoms in PD stem from decades of progressive neurodegeneration selectively afflicting discrete neuronal populations along a caudo-rostral axis. However, recapitulating this spatiotemporal neurodegenerative pattern in rodents has been unsuccessful. The purpose of this study was to generate such animal PD models and delineate mechanism underlying the ascending neurodegeneration. Neuroinflammation, oxidative stress, and neuronal death in mice brains were measured at different times following a single systemic injection of lipopolysaccharide (LPS). We demonstrate that LPS produced an ascending neurodegeneration that temporally afflicted neurons initially in the locus coeruleus (LC), followed by substantia nigra, and lastly the primary motor cortex and hippocampus. To test the hypothesis that LPS-elicited early loss of noradrenergic LC neurons may underlie this ascending pattern, we used a neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to deplete brain norepinephrine. DSP-4 injection resulted in a time-dependent ascending degenerative pattern similar to that generated by the LPS model. Mechanistic studies revealed that increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX2)-dependent superoxide/reactive oxygen species (ROS) production plays a key role in both LPS- and DSP-4-elicited neurotoxicity. We found that toxin-elicited chronic neuroinflammation, oxidative neuronal injuries, and neurodegeneration were greatly suppressed in mice deficient in NOX2 gene or treated with NOX2-specific inhibitor. Our studies document the first rodent PD model recapturing the ascending neurodegenerative pattern of PD patients and provide convincing evidence that the loss of brain norepinephrine is critical in initiating and maintaining chronic neuroinflammation and the discrete neurodegeneration in PD.

Keywords

Parkinson’s diseases Progressive neurodegeneration Chronic neuroinflammation Norepinephrine depletion Oxidative and nitrosylative neuronal injuries 

Abbreviations

3-NT

3-nitrotyrosine

4-HNE

4-hydroxy-2-nonenal

CPu

caudate-putamen

CD11b

integrin αM chain

DA

dopamine

DAMPs

danger-associated molecular patterns

DHE

dihydroethidium

DPI

diphenyleneiodonium

DSP-4

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine

FDG

fludeoxyglucose

Hip

hippocampus

Iba-1

ionized calcium-binding adapter molecule-1

LC

locus coeruleus

LPS

lipopolysaccharide

MCtx

motor cortex

NE

norepinephrine

NeuN

neuronal nuclei

NOX2

nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2

PBR

peripheral benzodiazepine receptor

PET

positron emission tomography

ROS

reactive oxygen species

SNpc

substantia nigra pars compacta

SUV

standard uptake value

TH

tyrosine hydroxylase

TSPO

translocator protein

VTA

ventral tegmental area

Notes

Acknowledgments

This research was supported through the Intramural Research Program at the National Institute of Environmental Health Sciences in the National Institutes of Health, USA. We thank Anthony Lockhart for assistance with animal colony management and maintenance.

Compliance with ethical standards

Disclosures

The authors declare that they have no actual or potential competing financial interests.

Supplementary material

12035_2018_1235_MOESM1_ESM.pdf (675 kb)
ESM 1 (PDF 675 kb)

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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2018

Authors and Affiliations

  • Sheng Song
    • 1
  • Lulu Jiang
    • 1
    • 2
  • Esteban A. Oyarzabal
    • 1
    • 3
  • Belinda Wilson
    • 1
  • Zibo Li
    • 3
  • Yen-Yu Ian Shih
    • 3
  • Qingshan Wang
    • 1
    • 4
    Email author
  • Jau-Shyong Hong
    • 1
    Email author
  1. 1.Neuropharmacology Section, Neurobiology Laboratory, National Institute of Environmental Health SciencesNational Institutes of HealthNorth CarolinaUSA
  2. 2.Institute of Toxicology, School of Public HealthShandong UniversityJinanChina
  3. 3.Biomedical Research Imaging CenterUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Department of Toxicology, School of Public HealthDalian Medical UniversityDalianChina

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