nitroarginine and Encephalitis

In this study we investigated the effect of immunostimulation on intracellular ATP level in rat glial cells. Rat primary astrocytes or C6 glioma cells were treated for 48 h with IFN-gamma, LPS or IFN-gamma plus LPS. These treatments increased NO production from the cells and a synergistic increase in NO production was observed with IFN-gamma plus LPS. Intracellular ATP level was decreased to about half the control level at the highest concentration of IFN-gamma (100 U/ml) plus LPS (1 microg/ml) without affecting cell viability. The level of intracellular ATP was inversely correlated with the extent of NO production from the glial cells. The increase in NO production is at least 6 h ahead of the initiation of ATP depletion, and NOS inhibitor N(G)-nitro-L-arginine (NNA) or Nomega-nitro-L-arginine methyl ester (L-NAME) inhibited NO production and ATP depletion. Exogenous addition of peroxynitrite generator 3-morpholinosydnonimine (SIN-1) and to a lesser extent NO generator S-nitroso-N-acetylpenicillamine (SNAP) depleted intracellular ATP level in a dose-dependent manner. The results from the present study imply that immunostimulation of rat glial cells decreases the intracellular ATP level without affecting cell viability. Considering the role of astrocytes as an essential regulator of the extracellular environment in the brain, the immunostimulation-induced decrease in intracellular ATP level may participate in the pathogenesis of various neurological diseases.

Topics: Adenosine Triphosphate; Animals; Animals, Newborn; Astrocytes; Central Nervous System; Dose-Response Relationship, Drug; Encephalitis; Enzyme Inhibitors; Inflammation Mediators; Interferon-gamma; Intracellular Fluid; L-Lactate Dehydrogenase; Lipopolysaccharides; Molsidomine; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Penicillamine; Rats; Rats, Sprague-Dawley; S-Nitroso-N-Acetylpenicillamine; Tumor Cells, Cultured

The pathogenesis of Parkinson's disease is still poorly understood. To address the hypothesis that immune-mediated events, such as microglial activation, may be involved in the dopaminergic neurodegeneration, we have studied the effect that intranigral injection of the immunostimulant lipopolysaccharide has on monoaminergic neurotransmitters in rats. Activation of microglial cells, visualized by immunohistochemistry with a specific monoclonal antibody, was already obvious 2 days after injection. In relation to the biochemical parameters studied, we found a significant decrease of dopamine levels in both the substantia nigra and striatum up to at least 21 days after intranigral injection of lipopolysaccharide. This result was supported by the decrease in tyrosine hydroxylase activity and the loss of tyrosine hydroxylase-positive neuronal bodies, shown by immunohistochemistry. These alterations of the dopaminergic system did not reverse during the interval studied (21 days); conversely, the serotoninergic system suffered only transient damage. In addition, we found that the neurotoxic effect of lipopolysaccharide was not mediated by nitric oxide. Based on our results we suggest that the nigrostriatal dopaminergic system is susceptible to damage by inflammatory events and that these may be implicated in neurodegeneration processes such as Parkinson's disease.

Topics: Animals; Corpus Striatum; Dopamine; Encephalitis; Female; Hydroxyindoleacetic Acid; Immunohistochemistry; Injections; Lipopolysaccharides; Nitroarginine; Rats; Rats, Wistar; Serotonin; Substantia Nigra; Tyrosine 3-Monooxygenase