Dexamethasone protects neonatal hypoxic-ischemic brain injury via L-PGDS-dependent PGD₂-DP₁-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 D2 (PGD₂)-DP₁-pERK mediated signaling pathway.

Methods: Dexamethasone and inhibitors were administered via intracerebroventricular (i.c.v) injections into 10-day-old rat brains. Levels of LPGD₂, D prostanoid (DP₁) receptor, pERK1/2 and PGD₂ 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 PGD₂. Dexamethasone also selectively increased isoform pERK-44 level in the neonatal rat brains. Inhibitors of L-PGDS (SeCl4), DP₁ (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-PGD₂-DP₁- pERK mediated pathway underlies the neuroprotective effects of dexamethasone pretreatment in neonatal HI brain injury.