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

Pablo J Gonzalez-Rodriguez,Lubo Zhang,Fabian Martinez,Yong Li

doi:10.1371/journal.pone.0114470

Pablo J Gonzalez-Rodriguez, Lubo Zhang + Show 2 more

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https://doi.org/10.1371/journal.pone.0114470

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Journal: PloS one	Publication Date: Dec 4, 2014
Citations: 34	License type: CC BY 4.0

Affiliation: Loma Linda University

Abstract

Background and PurposeGlucocorticoids 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.MethodsDexamethasone and inhibitors were administered via intracerebroventricular (i.c.v) injections into 10-day-old rat brains. Levels of L-PGD2, 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.ResultsDexamethasone 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.ConclusionInteraction of glucocorticoids-GR signaling and L-PGDS-PGD2-DP1-pERK mediated pathway underlies the neuroprotective effects of dexamethasone pretreatment in neonatal HI brain injury.

Highlights

Perinatal hypoxia-ischemia (HI) brain injury is a leading cause of acute mortality and chronic disability in newborns with an incidence of 1–8 cases per 1000 births, affecting 60% of preterm infants, which causes long-lasting morbidity, including cerebral palsy, seizure, and cognitive retardation in infants and children [1, 2]
We present the evidence of a novel finding that dexamethasone pretreatment protects against hypoxic-ischemic brain injury via activation of L-PGDSdependent prostaglandin D2 (PGD2)-DP1 signaling in the neonatal rat brain, of which pERK-44 acts as the major downstream kinase effector
PGD2 up-regulation accounted for the dexamethasone pretreatment induced neuroprotective effects against neonatal HI brain injury via activation of DP1 receptor; 3. pERK-44 acted as the major downstream effector in PGD2-DP1 receptor mediated signaling pathway; 4. at the molecular level, interaction of glucocorticoids-glucocorticoid receptor (GR) signaling and lipocalin-type prostaglandin D synthase (L-PGDS)-PGD2-DP1-pERK pathway afforded the protection of dexamethasone pretreatment against neonatal HI brain injury

Summary

Introduction

Perinatal hypoxia-ischemia (HI) brain injury is a leading cause of acute mortality and chronic disability in newborns with an incidence of 1–8 cases per 1000 births, affecting 60% of preterm infants, which causes long-lasting morbidity, including cerebral palsy, seizure, and cognitive retardation in infants and children [1, 2]. Our recent studies revealed that dexamethasone pretreatment confers neuroprotective effects and reverses maternal hypoxia exposure induced enhanced susceptibility to neonatal HI brain injury [6]. 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. Dexamethasone 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 blocked dexamethasone-mediated neuroprotective effects against HI brain injury in neonatal rat brains. Conclusion: Interaction of glucocorticoids-GR signaling and L-PGDS-PGD2-DP1pERK mediated pathway underlies the neuroprotective effects of dexamethasone pretreatment in neonatal HI brain injury

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