Protection by vascular prostaglandin E2 signaling in hypoxic–ischemic encephalopathy

Abstract

Hypoxic ischemic encephalopathy (HIE) in neonates is a leading cause of neurological impairment. Significant progress has been achieved investigating the pathologic contributions of excitotoxicity, oxidative stress, and neuroinflammation to cerebral injury in HIE. Less extensively investigated has been the contribution of vascular dysfunction, and whether modulation of cerebral perfusion may improve HIE outcome. Here, we investigated the function of the prostaglandin E2 (PGE2) EP4 receptor, a vasoactive Gαs-protein coupled receptor (GPCR), in rodent models of neonatal HIE. The function of PGE2 signaling through the EP4 receptor was investigated using pharmacologic and conditional knockout genetic strategies in vivo in rodent models of HIE. Pharmacologic activation of the EP4 receptor with a selective agonist was significantly cerebroprotective both acutely and after 7 days. Measurement of cerebral perfusion during and after hypoxia-ischemia demonstrated that EP4 receptor activation improved cerebral perfusion in both the contralateral and ipsilateral hypoxic-ischemic hemispheres. To test whether vascular EP4 signaling exerted a critical function in HIE injury, cell specific conditional knockout mouse pups were generated in which endothelial EP4 receptor was selectively deleted postnatally. VE-Cadherin Cre-ERT2;EP4lox/lox pups demonstrated significant increases in cerebral injury as compared to VE-Cadherin CreERT2;EP4+/+ control littermates, indicating that endothelial EP4 signaling is protective in HIE. Our findings identify vascular PGE2 signaling through its EP4 receptor as protective in HIE. Given the pharmacologic accessibility of endothelial EP4 GPCRs, these data support further investigation into novel approaches to target cerebral perfusion in neonatal HIE.

Prostaglandin E2 EP4 Receptor Activation Attenuates Neuroinflammation and Early Brain Injury Induced by Subarachnoid Hemorrhage in Rats

“…These results are consistent with some previous studies demonstrating that the activation of EP4 receptor shows neuroprotective effects on other CNS insults such as cerebral ischemia [23, 24], hypoxic-ischemic encephalopathy (HIE) [25], neurotoxicity induced brain injury [26] and Alzheimer ’ s disease [21]. …”

“…In vivo and in vitro studies have proved that activation of EP4 receptor by exogenous EP4 selective agonist suppresses microglial inflammatory response to Aβ 42 peptides and lipopolysaccharide while conditional deletion of microglial EP4 conversely increases inflammatory gene expression [21, 22]. A broad variety of experimental neuropathological models associated with inflammation are also alleviated by the activation of EP4 receptor, including cerebral ischemia [23, 24], hypoxic-ischemic encephalopathy (HIE) [25], neurotoxicity induced brain injury [26] and Alzheimer’s disease [21]. …”

Anti-Inflammatory and Neuroprotective Effects of PGE2 EP4 Signaling in Models of Parkinson’s Disease

“…This indicates that the neuroprotective effect of the EP4 agonist is likely independent of MPTP-associated neuroinflammation. We have shown previously that EP4 receptors are expressed by neurons as well as endothelial cells in the brain, and EP4 elicits neuroprotection in the context of ischemia [35-37]. The data from this study suggests that systemically administered EP4 receptor agonist crosses the blood brain barrier and may directly interact with neuronal or endothelial EP4 receptors, activating intracellular pathways in a timely manner to prevent MPTP-induced degeneration of dopaminergic neurons, a process that normally take several days.…”

The role of inflammation in perinatal brain injury

“…The figure is a summary based on multiple experimental and clinical studies. 4,17,19,21,28,31–33,57–59,122,125 Abbreviations: C, complement; CD, cluster of differentiation; COX, cyclooxygenase; DPR, prostaglandin D receptor; EPR, prostaglandin E receptor; FasL, Fas ligand; iNOS, inducible NOS; LIF, leukemia inhibitory factor; MMP, matrix metalloproteinase; nNOS, neuronal NOS; NOS, nitric oxide synthase; PG, prostaglandin; SOCS, suppressor of cytokine signalling; TGF, transforming growth factor; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor. Chemokines are abbreviated according to the new classification.…”