We showed that COX-1 KO mice have a significant reduction in brain inflammatory response and oxidative damage after LPS. The protection was attributed to attenuation of microglial activation, a critical process in the initiation of inflammation, and to a reduction of inflammatory mediators such as PGE2, IL-1beta, TNF-alpha, and of protein oxidation, critical factors contributing to the secondary progression of the inflammatory reaction and oxidative damage. Translocation and activation of nuclear factor-kappaB (NF-kB) and signal transducer s and activators of transcription 3 (STAT3), important factors for signaling events during an inflammatory response, were also reduced in COX-1 KO mice. Administration of SC-560, a specific COX-1 inhibitor, prior to LPS injection, also attenuated the neuroinflammatory response by decreasing brain levels of PGE2, PGD2, PGF2, and TXB2, as well as the expression of pro-inflammatory cytokines and chemokine. In contrast, the LPS-induced expression of pro-inflammatory cytokines and reactive oxygen species-generating enzymes, such as iNOS and NADPH oxidase, was increased in COX-2 KO compared to WT mice. Mice treated for 6 weeks with celecoxib, a selective COX-2 inhibitor, prior to LPS also exhibited higher brain levels of IL-1 and p67phox, compared to non-treated wild type mice. Since chemokines are involved in the trafficking and the recruitment of leukocytes into the inflamed brain, we hypothesized that COX-2 deletion can alter the blood-brain barrier (BBB) integrity. Using quantitative magnetic resonance imaging, we found that LPS-induced BBB disruption was increased in COX-2 KO mice, compared to their respective WT.[unreadable] These results suggest that COX-1 plays an important role in the regulation of microglial inflammatory responses in the central nervous system and that COX-1 inhibition might be beneficial to reduce the effects of neuroinflammation and related oxidative stress. In contrast, selective COX-2 inhibition may worsen neuroinflammatory responses, suggesting a neuroprotective function of COX-2 derived products and that selective inhibition of COX-2 is not beneficial in neurodegenerative disease with a marked inflammatory component.