Dexamethasone Protects Neonatal Hypoxic-Ischemic Brain Injury via L-PGDS-Dependent PGD(2)-DP(1)-pERK Signaling Pathway

BACKGROUND AND PURPOSE: Glucocorticoids pretreatment confers protection against neonatal hypoxic-ischemic (HI) brain injury. However, the molecular mechanism remains poorly elucidated. We tested the hypothesis that glucocorticoids protect against HI brain injury in neonatal rat by stimulation of lipocalin-type prostaglandin D synthase (L-PGDS)-induced prostaglandin D(2) (PGD(2))-DP(1)-pERK mediated signaling pathway. METHODS: Dexamethasone and inhibitors were administered via intracerebroventricular (i.c.v) injections into 10-day-old rat brains. Levels of L-PGD(2), D prostanoid (DP(1)) receptor, pERK1/2 and PGD(2) were determined by Western immunoblotting and ELISA, respectively. Brain injury was evaluated 48 hours after conduction of HI in 10-day-old rat pups. RESULTS: Dexamethasone pretreatment significantly upregulated L-PGDS expression and the biosynthesis of PGD(2). Dexamethasone also selectively increased isoform pERK-44 level in the neonatal rat brains. Inhibitors of L-PGDS (SeCl(4)), DP(1) (MK-0524) and MAPK (PD98059) abrogated dexamethasone-induced increases in pERK-44 level, respectively. Of importance, these inhibitors also blocked dexamethasone-mediated neuroprotective effects against HI brain injury in neonatal rat brains. CONCLUSION: Interaction of glucocorticoids-GR signaling and L-PGDS-PGD(2)-DP(1)-pERK mediated pathway underlies the neuroprotective effects of dexamethasone pretreatment in neonatal HI brain injury.