Signaling via the prostaglandin E2 receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia

Abstract

Stroke is the third leading cause of death in the United States. Fewer than 5% of patients benefit from the only intervention approved to treat stroke. Thus, there is an enormous need to identify new therapeutic targets. The role of inducible cyclooxygenase (COX-2) activity in stroke and other neurologic diseases is complex, as both activation and sustained inhibition can engender cerebral injury. Whether COX-2 induces cerebroprotective or injurious effects is probably dependent on which downstream prostaglandin receptors are activated. Here, we investigated the function of the PGE 2 receptor EP4 in a mouse model of cerebral ischemia. Systemic administration of a selective EP4 agonist after ischemia reduced infarct volume and ameliorated long-term behavioral deficits. Expression of EP4 was robust in neurons and markedly induced in endothelial cells after ischemiareperfusion, suggesting that neuronal and/or endothelial EP4 signaling imparts cerebroprotection. Conditional genetic inactivation of neuronal EP4 worsened stroke outcome, consistent with an endogenous protective role of neuronal EP4 signaling in vivo. However, endothelial deletion of EP4 also worsened stroke injury and decreased cerebral reperfusion. Systemic administration of an EP4 agonist increased levels of activated eNOS in cerebral microvessels, an effect that was abolished with conditional deletion of endothelial EP4. Thus, our data support the concept of targeting protective prostaglandin receptors therapeutically after stroke. IntroductionStroke is the third leading cause of death after cardiovascular disease and cancer, and stroke survivors have a 30%-50% chance of losing functional independence (1). Treatment with recombinant tPA, a thrombolytic agent, is the only approved therapy for acute stroke; however, less than 5% of stroke patients benefit from this intervention (2), in large part because of the limited time window of administration and the risk of hemorrhagic transformation. Translational attempts to validate neuroprotective strategies in the early poststroke setting have been uniformly unsuccessful, even in cases of compelling preclinical animal data. Although many reasons have been raised for this lack of success, there is consensus that single agents targeting early short-lived components of the neurotoxic cascade may not be effective (3). Thus, there is a crucial need to identify new interventions that can be therapeutically implemented after stroke.The cyclooxygenases COX-1 and COX-2 catalyze the first committed step in the formation of prostaglandins PGE 2 , PGD 2 , PGF 2a , TXA 2 , and PGI 2 , which activate distinct classes of GPCRs (reviewed in ref. 4). Cyclooxygenase activation and prostaglandin receptor signaling elicits significant injury in models of cerebral ischemia and related models of spinal cord and brain trauma, and also contributes to neurodegeneration in models of Parkinson disease, amyotrophic lateral sclerosis, and Alzheimer disease (reviewed in ref. 5). Thus, pathological induction of cyclooxygenase/prostagla...

The Prostanoid EP4 Receptor and Its Signaling Pathway

“…Moreover, they observed that cognitive function of mice in an Alzheimer's disease model was improved by genetic and pharmacological inhibition of EP4 (Hoshino et al, 2012). In contrast, Liang et al (2011) reported that an EP4 receptor agonist exerted a protective effect against cerebral ischemia injury in mice. Deletion of neuronal EP4 increased the severity of cerebral injury, as did endothelial deletion of EP4.…”

G-Protein–Coupled Receptor 91 and Succinate Are Key Contributors in Neonatal Postcerebral Hypoxia-Ischemia Recovery

“…Our findings are consistent with a robust expression of EP 4 in neurons and in endothelial cells after cerebral ischemia, suggesting a protective sensory cellular mechanism. 61 Along these lines, PGE 2 and EP 4 agonists have recently been patented as a method to treat ischemic episodes (US 2010/0267826 A1).…”

The immunology of neurodegeneration

“…Recently an exciting approach to studying the effect of prostaglandins in the brain was described in a stroke model (31). The COX-2 product prostaglandin E2 can bind to four different prostanoid receptors making it difficult to understand how COX-2 inhibitors, which seem to strongly reduce risk of AD (32) and PD (33), work in the brain.…”

“…The COX-2 product prostaglandin E2 can bind to four different prostanoid receptors making it difficult to understand how COX-2 inhibitors, which seem to strongly reduce risk of AD (32) and PD (33), work in the brain. Liang and coworkers showed that genetic deletion of prostanoid receptor 4 in neurons worsened stroke injury and decreased cerebral perfusion, pointing to a beneficial effect of this receptor in neurons (31). Clearly, this is a direction in which the field of neurodegeneration has to move in order to gain a more complete understanding of the complex action of immune factors in neuronal distress and degeneration.…”