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

Neuroscience. 2002;110(1):49-58. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cell Death / drug effects
  • Cell Death / physiology*
  • Dopamine / biosynthesis*
  • Encephalitis / chemically induced
  • Encephalitis / enzymology*
  • Encephalitis / physiopathology
  • Fluorescent Dyes
  • Glial Fibrillary Acidic Protein / drug effects
  • Glial Fibrillary Acidic Protein / metabolism
  • Hydroxyl Radical / metabolism
  • Lipopolysaccharides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • NADPH Dehydrogenase / metabolism
  • 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
  • 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


  • Fluorescent Dyes
  • Glial Fibrillary Acidic Protein
  • Lipopolysaccharides
  • Peroxynitrous Acid
  • Nitric Oxide
  • Hydroxyl Radical
  • Nitric Oxide Synthase
  • Tyrosine 3-Monooxygenase
  • NADPH Dehydrogenase
  • Dopamine