However, in these studies, where the toxins directly damage neurons, COX 2 mediated cytotoxicity does not appear to be linked to the inflammatory response. On the other hand, pre treatment with COX 2 inhibitors inhibitor purchase or genetic deletion of COX 2 has been shown to increase seizure activity and neuronal damage in response to kainate, and to exacerbate endotoxin induced ocular inflammation and tissue damage in ConA and acetaminophen induced hepatotoxicity. Another study reported, in support of our obser vations, that selective pharmacological inhibition of COX 2 with NS 398 increases the transcription of inflam matory genes in vascular associated brain cells and parenchymal microglia after systemic injection of LPS.

While these conflicting data highlight the importance of investigating the Inhibitors,Modulators,Libraries distinct roles of COX 1 and COX 2 in physiology and pathology, our findings suggest that COX 2 derived products selec tively mediate a protective Inhibitors,Modulators,Libraries effect in the development and or the resolution of inflammation in the brain after endo toxin activation of the innate Inhibitors,Modulators,Libraries immune system. In this regard, a recent review emphasizes that COX 2 mediates neuroprotection via specific anti inflammatory lipid mediators. Furthermore, Gilroy and colleagues dem onstrated that selective COX 2 inhibitors, by blocking the production of PGE2 and PGD2, disturbed the resolution phase of inflammation, leading to delay in return to homeostasis. COX 1 protein levels were not significantly changed by LPS in either COX 2 or celecoxib treated mice compared to COX 2 mice, indicating that the increased neuroin flammatory response was not due to an increased com pensatory expression of COX 1 in response to LPS when COX 2 is either genetically abrogated or pharmacologi cally inhibited.

Increases in microglial activation and in the induction of cytokines and chemokines in the COX 2 mice could contribute Inhibitors,Modulators,Libraries Inhibitors,Modulators,Libraries to the susceptibility to LPS induced damage. Overexpression of chemokines, small pleiotropic chemoattractant cytokines that promote leu kocytes activation http://www.selleckchem.com/products/Y-27632.html and migration, has been recently impli cated in many neurological disorders including multiple sclerosis, and Alzheimers disease. The overexpres sion of chemokines observed in the COX 2 mice after LPS may increase the leukocytes and monocytes recruit ment in the inflamed brain and cause neuronal damages, in the absence of a switch off mechanism. The increased expression of cytokines could be due to the incapacity of the tissue to resolve the inflammation, leading to a persist ent activation of the inflammatory cascade. One possibil ity is that COX 2 deletion or inhibition leads to a reduction in anti inflammatory mediators or neuro trophic factors, which would impair the brain ability to resolve the inflammation.