Recently we proposed that COX-2 induction precedes expression of HO-I in ischemic preconditioned rat brain. In the current Study, we investigated the molecular mechanism by which prostaglandin E-2, one of COX-2 metabolites, induces HO-1 in rat C6 brain cells. We demonstrated that concentration of PGE(2) increased HO-1 expression in C6 cells in vitro. The effects of PGE(2) were mimicked by PGE(2) receptor EP2 agonists, 11-deoxy PGE(2), and cAMP analog, dibutyl-cAMP. HO-1 expression by PGE2 Was inhibited by LY294002, PI3K inhibitor and H89, PKA inhibitor. The EP2-specific antagonist, AH8006 also inhibited PGE(2)-mediated HO-1 expression in a concentration-dependent manner. Finally, PGE2 inhibited GOX-induced apoptosis as assayed by FACS analysis or DNA strand breaks assay, and this cell death was reversed by ZnPPIX, HO-1 inhibitor. In addition to HO-I induction, PGE2 also increased phosphorylation of Bid by PKA- and PI3K-depednent manner. Taken together, we conclude that PGE2 induces HO-1 protein expression through PKA and PI3K signaling pathways via EP2 receptor in C6 cells. The induction of HO-1 along with increase of p-Bad by PGE2 is responsible for anti-apoptosis against oxidant stress. (C) 2009 Elsevier Inc. All rights reserved.