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...

Designing cost-effective and highly active oxygen evolution reaction (OER) electrocatalyst is the critical for large scale hydrogen production from electrocatalytic water splitting. Herein, Fe and P dual-doped nickel carbonate hydroxide/carbon...

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Background and Purpose To test the hypothesis that angiotensin‐(1‐7) [Ang‐(1‐7)] may attenuate abdominal aortic aneurysm (AAA) via inhibiting vascular inflammation, extracellular matrix degradation, and smooth muscle cell (SMC) apoptosis, an animal model of AAA was established by angiotensin II (Ang II) infusion to apolipoprotein E‐knockout (ApoE‐/‐) mice. Experimental Approach All mice and cultured SMCs or macrophages were divided into control, Ang II‐treated, Ang II + Ang‐(1‐7)‐treated, Ang II + Ang‐(1‐7) + A779‐treated and Ang II + Ang‐(1‐7) + PD123319‐treated groups respectively. In vivo, aortic mechanics and serum lipids were assessed. Ex vivo, AAA were examined by histology, immunohistochemistry and zymography. Cultured cells were analysed by RT‐PCR, western blots and TUNEL assays. Key Results In vivo, Ang‐(1‐7) reduced the incidence and severity of AAA induced by Ang II infusion, by inhibiting macrophage infiltration, attenuating expression of IL‐6, TNF‐α, CCL2 and MMP2, and decreasing SMC apoptosis in abdominal aortic tissues. Addition of A779 or PD123319 reversed Ang‐(1‐7)‐mediated beneficial effects on AAA. In vitro, Ang‐(1‐7) decreased expression of mRNA for IL‐6, TNF‐α, and CCL2 induced by Ang II in macrophages. In addition, Ang‐(1‐7) suppressed apoptosis and MMP2 expression and activity in Ang II‐treated SMCs. These effects were accompanied by inhibition of the ERK1/2 signalling pathways via Ang‐(1‐7) stimulation of Mas and AT2 receptors. Conclusion and Implications Ang‐(1‐7) treatment attenuated Ang II‐induced AAA via inhibiting vascular inflammation, extracellular matrix degradation, and SMC apoptosis. Ang‐(1‐7) may provide a novel and promising approach to the prevention and treatment of AAA.