Neuroprotective Function of the PGE₂EP2 Receptor in Cerebral Ischemia

Abstract

The cyclooxygenases COX-1 and COX-2 catalyze the first committed step of prostaglandin synthesis from arachidonic acid. Previous studies in rodent stroke models have shown that the inducible COX-2 isoform promotes neuronal injury, and the administration of COX-2 inhibitors reduces infarct volume. We investigated the function of PGE 2 , a principal prostaglandin product of COX-2 enzymatic activity, in neuronal survival in cerebral ischemia. PGE 2 exerts its downstream effects by signaling through a class of four distinct G-proteincoupled EP receptors (for E-prostanoid: EP1, EP2, EP3, and EP4) that have divergent effects on cAMP and phosphoinositol turnover and different anatomical distributions in brain. The EP2 receptor subtype is abundantly expressed in cerebral cortex, striatum, and hippocampus, and is positively coupled to cAMP production. In vitro studies of dispersed neurons and organotypic hippocampal cultures demonstrated that activation of the EP2 receptor was neuroprotective in paradigms of NMDA toxicity and oxygen glucose deprivation. Pharmacologic blockade of EP2 signaling by inhibition of protein kinase A activation reversed this protective effect, suggesting that EP2-mediated neuroprotection is dependent on cAMP signaling. In the middle cerebral artery occlusion-reperfusion model of transient forebrain ischemia, genetic deletion of the EP2 receptor significantly increased cerebral infarction in cerebral cortex and subcortical structures. These studies indicate that activation of the PGE 2 EP2 receptor can protect against excitotoxic and anoxic injury in a cAMPdependent manner. Taken together, these data suggest a novel mechanism of neuroprotection mediated by a dominant PGE 2 receptor subtype in brain that may provide a target for therapeutic intervention.

Prostaglandin D2 DP1 receptor is beneficial in ischemic stroke and in acute exicitotoxicity in young and old mice

“…Various studies related to the protective role of prostaglandin E 2 receptors in paradigms of neuronal toxicity or animal models of neurodegeneration have indicated a potential role for increasing intracellular levels of cAMP and its downstream MAP kinase or protein kinase signaling pathways (McCullough et al 2004;Echeverria et al 2005;Ahmad et al 2006c). In parallel with these reports, Liang et al (2005) showed that DP1 receptor agonist BW245C protects against glutamate toxicity in cultured hippocampal neurons and organotypic slices in a cAMP-dependent fashion; they also showed that neurotoxic effects produced by glutamate in dispersed hippocampal neurons were abolished by protein kinase inhibitors.…”

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

“…At end-ischemia, the animal was briefly reanaesthetized and reperfusion was initiated by filament withdrawal. Monitoring of physiological variables and laser Doppler flowmetry (LDF) was performed in companion cohorts for all groups as previously described (n ¼ 5/ group in all genotypes and pharmacological cohorts; McCullough et al, 2004;Sawada et al, 2000).…”

“…Infarct size was expressed as a percentage of the contralateral hemisphere/structure after correcting for edema (McCullough et al, 2004;Sawada et al, 2000).…”

“…Regional CBF was measured with 14 C IAP autoradiography, as previously described (McCullough et al, 2004;Alkayed et al, 1998). Autoradiographic images representing 5 coronal levels ( þ 2, þ 1, 0, À1, and À2 mm from bregma, 3 images each) were digitized and regional CBF determined by image analysis software (Inquiry, Loats Associates).…”

Glutamate receptor and transporter modifications in rat organotypic hippocampal slice cultures exposed to oxygen–glucose deprivation: The contribution of cyclooxygenase-2

“…indicating that the presence of meloxicam, probably acting on COX-2 inhibition, results in a neuroprotective effect on different models of cerebral ischemia (Nakayama et al, 1998;McCullough et al, 2004;Fathali et al, 2010), where glutamate excitotoxicity plays a critical role (Lipton, 1999;Campos et al, 2011). COX-2 has been hypothesized to attenuate glutamate excitotoxicity and, consequently, Ca 2+ influx, by indirectly modulating transcription of the ionotropic glutamatergic AMPA/KA and NMDA receptors based on COX-2-deficient mice assays (Caracciolo et al, 2011).…”