Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration.
The loss of dopaminergic neurones in the substantia nigra with Parkinson's disease may result from inflammation-induced proliferation of microglia and reactive macrophages expressing inducible nitric oxide synthase (iNOS). We have investigated the effects of the supranigral administration of lipopolysaccharide on iNOS-immunoreactivity, 3-nitrotyrosine formation and tyrosine hydroxylase-immunoreactive neuronal number, and retrogradely labelled fluorogold-positive neurones in the ventral mesencephalon in male Wistar rats. Following supranigral lipopolysaccharide injection, 16-18 h previously, there was intense expression of NADPH-diaphorase and iNOS-immunoreactivity in non-neuronal, macrophage-like cells. This was accompanied by intense expression of glial fibrillary acidic protein-immunoreactive astrocytosis in the substantia nigra. There were also significant reductions in the number of tyrosine hydroxylase(50-60%)- and fluorogold (65-75%)-positive neurones in the substantia nigra. In contrast, tyrosine hydroxylase-immunoreactivity in the ventral tegmental area was not altered. Pre-treatment of animals with the iNOS inhibitor, S-methylisothiourea (10 mg kg(-1), i.p.), led to a significant reduction of lipopolysaccharide-induced cell death. Similar reduction of tyrosine hydroxylase-immunoreactivity and fluorogold-labelled neurones in the substantia nigra following lipopolysaccharide administration suggests dopaminergic cell death rather than down-regulation of tyrosine hydroxylase. We conclude that the expression of iNOS- and 3-nitrotyrosine-immunoreactivity and reduction of cell death by S-methylisothiourea suggest the effects of lipopolysaccharide may be nitric oxide-mediated, although other actions of lipopolysaccharide (independent of iNOS induction) cannot be ruled out.
Iravani
M M
MM
Wolfson Centre for Age-Related Diseases, Neurodegenerative Disease Research Centre, Guy's, King's and St Thomas' School of Biomedical Sciences, Hodgkin Building, Guy's Campus, King's College, London SE1 1UL, UK.
Kashefi
K
K
Mander
P
P
Rose
S
S
Jenner
P
P
D000818:Animals; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000096:biosynthesis*; D004660:Encephalitis / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D005456:Fluorescent Dyes; D005904:Glial Fibrillary Acidic Protein / Q000187:drug effects / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010300:Parkinson Disease / Q000201:enzymology* / Q000503:physiopathology; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
D005456:Fluorescent Dyes; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D017665:Hydroxyl Radical; D019001:Nitric Oxide Synthase; D014446:Tyrosine 3-Monooxygenase; D009252:NADPH Dehydrogenase; D004298:Dopamine