Abstract
Microsomal prostaglandin (PG) E synthase-1 (mPGES-1) is an inducible terminal enzyme in the synthetic pathway for PGE2, which has been demonstrated to participate in many peripheral pathological inflammatory processes. Recently, we demonstrated that mPGES-1 also has a role in brain inflammation, such as that following cerebral ischemia. The expressions of mPGES-1 and cyclooxygenase-2 (COX-2) were induced and co-localized in neurons, microglia and endothelial cells in the cerebral cortex after transient focal ischemia. Using mPGES-1 knockout (KO) mice in which the postischemic PGE2 production in the cortex was completely absent, we found that the ischemic injuries were reduced compared to those in wild-type (WT) mice. Furthermore, the ameliorated symptoms observed in KO mice after ischemia were reversed to almost the same severity as in WT mice by intracerebroventricular injection of PGE2 into KO mice, suggesting the involvement of mPGES-1 in the exaggeration of ischemic injury through PGE2 production. The induction and involvement of mPGES-1 in neurotoxicity were also observed in a glutamate-induced excitotoxicity model using rodent hippocampal slices. Glutamate increased the expression of mPGES-1 and production of PGE2. The protective effect of NS-398, an inhibitor of COX-2, on the excitotoxicity observed in WT slices was completely abolished in mPGES-1 KO slices, which showed less excitotoxicity than WT slices. In the transient focal ischemia model, injection of NS-398 reduced not only ischemic PGE2 production, but also ischemic injuries in WT mice, but not in mPGES-1 KO mice, which showed less dysfunction than WT mice. Our observations suggest that mPGES-1 is a critical determinant of postischemic neurological dysfunctions and that mPGES-1 and COX-2 are co-induced and co-localized by excess glutamate and act together to exacerbate stroke injury through excessive PGE2 production. Considering that COX-2 inhibitors may non-selectively suppress the production of many types of prostanoids that are essential for normal physiological function of the brain and that a large number of epidemiological studies have provided evidence of an increased cardiovascular risk associated with the use of COX-2, an mPGES-1 inhibitor may prove to be an injury-selective inhibitor with fewer side effects. Thus, the results from mPGES-1 KO mice suggest that mPGES-1 is a promising novel target for the treatment of human stroke.
