Article

Lipopolysaccharide-induced dopaminergic cell death in rat midbrain slice cultures: role of inducible nitric oxide synthase and protection by indomethacin.

Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Journal of Neurochemistry (impact factor: 4.06). 10/2003; 86(5):1201-12. pp.1201-12
Source: PubMed

ABSTRACT Glial cell activation associated with inflammatory reaction may contribute to pathogenic processes of neurodegenerative disorders, through production of several cytotoxic molecules. We investigated the consequences of glial activation by interferon-gamma (IFN-gamma)/lipopolysaccharide (LPS) in rat midbrain slice cultures. Application of IFN-gamma followed by LPS caused dopaminergic cell death and accompanying increases in nitrite production and lactate dehydrogenase release. Aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS), or SB203580, an inhibitor of p38 mitogen-activated protein kinase, prevented dopaminergic cell loss as well as nitrite production. SB203580 also suppressed expression of iNOS and cyclooxygenase-2 (COX-2) induced by IFN-gamma/LPS. A COX inhibitor indomethacin protected dopaminergic neurons from IFN-gamma/LPS-induced injury, whereas selective COX-2 inhibitors such as NS-398 and nimesulide did not. Notably, indomethacin was able to attenuate neurotoxicity of a nitric oxide (NO) donor. Neutralizing antibodies against tumour necrosis factor-alpha and interleukin-1beta did not inhibit dopaminergic cell death caused by IFN-gamma/LPS, although combined application of these antibodies blocked lactate dehydrogenase release and decrease in the number of non-dopaminergic neurons. These results indicate that iNOS-derived NO plays a crucial role in IFN-gamma/LPS-induced dopaminergic cell death, and that indomethacin exerts protective effect by mechanisms probably related to NO neurotoxicity rather than through COX inhibition.

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Keywords

attenuate neurotoxicity
 
COX inhibition
 
cytotoxic molecules
 
glial activation
 
Glial cell activation
 
IFN-gamma
 
IFN-gamma)/lipopolysaccharide
 
IFN-gamma/LPS
 
IFN-gamma/LPS-induced dopaminergic cell death
 
IFN-gamma/LPS-induced injury
 
indomethacin exerts protective effect
 
inducible nitric oxide synthase
 
inflammatory reaction
 
lactate dehydrogenase release
 
neurodegenerative disorders
 
nitric oxide
 
nitrite production
 
p38 mitogen-activated protein kinase
 
pathogenic processes
 
rat midbrain slice cultures