Striatal neuroinflammation promotes Parkinsonism in rats.
BACKGROUND
Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disorder with unknown cause, but it has been suggested that neuroinflammation may play a role in pathogenesis of the disease. Neuroinflammatory component in process of PD neurodegeneration was proposed by postmortem, epidemiological and animal model studies. However, it remains unclear how neuroinflammatory factors contribute to dopaminergic neuronal death in PD.


RESULTS
In this study, we analyzed the relationship among inducible nitric oxide synthase (iNOS)-derived NO, mitochondrial dysfunction and dopaminergic neurodegeneration to examine the possibility that microglial neuroinflammation may induce dopaminergic neuronal loss in the substantia nigra. Unilateral injection of lipopolysaccharide (LPS) into the striatum of rat was followed by immunocytochemical, histological, neurochemical and biochemical analyses. In addition, behavioral assessments including cylinder test and amphetamine-induced rotational behavior test were employed to validate ipsilateral damage to the dopamine nigrostriatal pathway. LPS injection caused progressive degeneration of the dopamine nigrostriatal system, which was accompanied by motor impairments including asymmetric usage of forelimbs and amphetamine-induced turning behavior in animals. Interestingly, some of the remaining nigral dopaminergic neurons had intracytoplasmic accumulation of alpha-synuclein and ubiquitin. Furthermore, defect in the mitochondrial respiratory chain, and extensive S-nitrosylation/nitration of mitochondrial complex I were detected prior to the dopaminergic neuronal loss. The mitochondrial injury was prevented by treatment with L-N(6)-(l-iminoethyl)-lysine, an iNOS inhibitor, suggesting that iNOS-derived NO is associated with the mitochondrial impairment.


CONCLUSIONS
These results implicate neuroinflammation-induced S-nitrosylation/nitration of mitochondrial complex I in mitochondrial malfunction and subsequent degeneration of the nigral dopamine neurons.
Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky, United States of America.
Dong-Young
DY
Choi
Mei
M
Liu
Randy L
RL
Hunter
Wayne A
WA
Cass
Jignesh D
JD
Pandya
Patrick G
PG
Sullivan
Eun-Joo
EJ
Shin
Hyoung-Chun
HC
Kim
Don M
DM
Gash
Guoying
G
Bing
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D004333:Drug Administration Routes; D042967:Electron Transport Complex I / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology*; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D015538:Nitrosation / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D025801:Ubiquitin / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
D008070:Lipopolysaccharides; D025801:Ubiquitin; D051844:alpha-Synuclein; D042967:Electron Transport Complex I; D004298:Dopamine