Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration

• Published in: Neuroscience Vol. 110; no. 1; pp. 49 - 58
• Main Authors: Iravani, M.M, Kashefi, K, Mander, P, Rose, S, Jenner, P
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.01.2002; Elsevier
• Subjects: Animals; Biological and medical sciences; Cell Count; Cell Death - drug effects; Cell Death - physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dopamine - biosynthesis; dopaminergic neurones; Encephalitis - chemically induced; Encephalitis - enzymology; Encephalitis - physiopathology; Fluorescent Dyes; Glial Fibrillary Acidic Protein - drug effects; Glial Fibrillary Acidic Protein - metabolism; Hydroxyl Radical - metabolism; inducible nitric oxide synthase; inflammation; lipopolysaccharide; Lipopolysaccharides - pharmacology; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Medical sciences; NADPH Dehydrogenase - metabolism; Neurology; Neurons - drug effects; Neurons - enzymology; Neurons - pathology; Nitric Oxide - metabolism; Nitric Oxide Synthase - drug effects; Nitric Oxide Synthase - metabolism; Oxidative Stress - drug effects; Oxidative Stress - physiology; Parkinson Disease - enzymology; Parkinson Disease - physiopathology; Parkinson’s disease; Peroxynitrous Acid - metabolism; Rats; Rats, Wistar; Substantia Nigra - drug effects; Substantia Nigra - enzymology; Substantia Nigra - physiopathology; Tyrosine 3-Monooxygenase - drug effects; Tyrosine 3-Monooxygenase - metabolism; 3-NT, 3-nitrotyrosine; PD, Parkinson’s disease; GFAP, glial fibrillary acidic protein; SN, substantia nigra; VTA, ventral tegmental area; ir, immunoreactive; IL-1β, interleukin-1β; NOARG, nitroarginine; inducible nitric oxide synthase; L-NAME, L- N(G)-nitroarginine methyl ester; AP, anterioposterior; PBS, phosphate-buffered saline; inflammation; TH, tyrosine hydroxylase; L, lateral; dopaminergic neurones; IFN-γ, interferon-γ; nNOS, neuronal NOS; 7-NI, 7-nitroindazole; TNF-α, tumour necrosis factor-α; MPP +, N-methyl-4-phenyl-dihydropyridinium; NOS, nitric oxide synthase; V, ventral; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA, 6-hydroxydopamine; SMT, S-methylisothiourea; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; lipopolysaccharide; FG, fluorogold; NADPH-d, reduced nicotinamide-adenine dinucleotide diaphorase; Parkinson’s disease; Nervous system diseases; Rat; Enzyme; Rodentia; Parkinson disease; Inflammation; Nitric-oxide synthase; Cerebral disorder; Vertebrata; Mammalia; Cell death; Animal; Nitric oxide; Central nervous system disease; Lipopolysaccharide; Dopaminergic neuron; Degenerative disease; Oxidoreductases; Extrapyramidal syndrome
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(01)00562-0

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.