Firstly, transcriptional regulation of COX-2 and mPGES-1 needs at

Firstly, transcriptional regulation of COX-2 and mPGES-1 needs at least 90 min (Cao et al., 2001 and Elmquist et al., 1997), and therefore cannot explain the behavioural responses to LPS challenge observed 30 min after administration (Swiergiel and Dunn, 2002). Secondly, selective inhibition of COX-2 only partially reduces the level of PGE2 during acute and chronic inflammation,

while indomethacin reduces PGE2 to undetectable levels (Langenbach et al., 1995): COX-1 may therefore contribute significantly to the local pool of PGE2 at the site of inflammation. Recent evidence also suggests that COX-1 and COX-2 have different functions in the brain as compared to the periphery. COX-1 is constitutively expressed in the brain, predominantly in microglia, and can be induced in endothelium during brain injury (Schwab et al., 2000). Both genetic TSA HDAC order ablation and pharmacological inhibition indicate an inflammatory role of COX-1 in the brain: this was elegantly demonstrated in COX-1

deficient mice that showed a less robust inflammatory response as compared to wild-type mice after intracerebral injection of LPS (Choi et al., 2008). Interestingly, COX-1 positive microglia are observed in various neurological diseases, including Alzheimer’s disease, Creutzfeldt Jacob disease and HIV associated with dementia, and correlate with disease severity and tissue damage (Choi et al., 2009). COX-2 is also constitutively expressed in the brain, and in particular in the hippocampus and cortical glutaminergic neurons (Choi et al., 2009). Despite the well-described direct see more neurotoxic effects, COX-2 has a potent anti-inflammatory function: intracerebral injection of LPS in COX-2 deficient mice results in a stronger inflammatory response and neuronal damage as compared to wild-type mice (Aid

et al., 2008). It is well known that a systemic LPS challenge impacts on microglia in the healthy brain without evidence of irreversible neuronal damage (Cunningham et al., 2005 and Dantzer and Kelley, 2007). Therefore, the behavioural changes Teicoplanin observed in our model, which were already observed 30 min after injection of LPS, may be explained by activation of constitutive COX-1 expressed by microglia. COX-2 inhibitors did not significantly reverse deficits in burrowing and open-field activity tested 3, 6 or 24 h after injection of LPS, while COX-1 inhibition reversed deficits in these behavioural responses at 3 h. Both piroximide and nimesulide have a short half life in mice, but based on their IC50 value, a dose of 10 mg/kg is expected to be functional at 6 h after injection (Hull et al., 2005 and Park et al., 2007). Our results are different from Swiergiel and Dunn who demonstrated that COX-1 plays an important role in the early changes in sickness behaviour, while COX-2 is more important at later time points, coinciding with the onset of a fever response (Swiergiel and Dunn, 2002). The latter study used a different behavioural test, i.e.

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