COX-2 expression and PGE2 production play important roles in inflammation related neurodegeneration. Reactive oxygen species (ROS) produced by activated microglia are deleterious to neurons. Emerging evidence also implies that intracellular ROS may act as signal transducing factors. In this study, we determined the role of ROS in the expression of COX-2 and production of prostaglandin E2 (PGE2) in rat microglia activated by LPS. LPS (5ng/ml) stimulated microglia to produce significant quantity of extracellular superoxide free radical that can be detected as early as 30 min following stimulation. Significant release of PGE2 was evident 24 hr after LPS stimulation. Pretreatment of microglia with superoxide dismutase (SOD)/catalase and the SOD/catalase mimetics significantly attenuated LPS-induced release of PGE2. Diphenylene iodonium (DPI), a non-specific NADPH oxidase inhibitor and NADPH oxidase gene mutant also decreased LPS induced PGE2 production, indicating NADPH oxidase is the source of the ROS involved. Furthermore, LPS-stimulated expression of COX-2, determined by RT-PCR analysis of COX mRNA and Western blot for its protein, were significantly reduced by pretreatment with SOD/catalase or SOD/catalase mimetics. SOD/mimetics show more potent effect on the inhibition of LPS-induced production of PGE2 and COX 2 expression than that of SOD/catalase. As a comparison, scavenging ROS showed no effect on LPS induced NO production in microglia. These results show that ROS, especially intracellular ones, play a potentially regulatory role in the expression of COX-2 and then the production of PGE2 during the activation process of microglia. In conclusion, reducing COX-2 expression and PGE2 production, through the inhibition of NADPH oxidase in microglia, is a potential strategy for therapeutic intervention of neurodegenerative diseases.
| Feng, Z-H; Wang, T-G; Li, D-D et al. (2002) Cyclooxygenase-2-deficient mice are resistant to 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced damage of dopaminergic neurons in the substantia nigra. Neurosci Lett 329:354-8 |
