Prostaglandin EP1 Receptor Contributes to Excitotoxicity and Focal Ischemic Brain Damage

Abstract

The clinical side effects associated with the inhibition of cyclooxygenase enzymes under pathologic conditions have recently raised concerns. A better understanding of neuroinflammatory mechanisms and neuronal survival requires knowledge of cyclooxygenase downstream pathways, especially PGE2 and its G-protein-coupled receptors. In this study, we postulate that EP1 receptor is one of the mechanisms that propagate neurotoxicity and could be a therapeutic target in brain injury. This hypothesis was tested by pretreating C57BL/6 wildtype mice with the EP1 receptor selective agonist ONO-DI-004 and the selective antagonist ONO-8713, followed by striatal unilateral NMDA injection. Results revealed that ONO-DI-004 increased NMDA-induced lesion volume up to 128.7 +/- 12.0%, while ONO-8713 significantly decreased lesion volume to 71.3 +/- 10.9%, as compared to the NMDA-control group. Neurotoxic EP1 receptor properties were also studied using C57BL/6 EP1 receptor knockout (EP1-/-) mice, which revealed a significant decrease to 74.5 +/- 8.2%, as compared to wildtype controls. The protective effect of the antagonist ONO-8713 was also tested in the EP1-/- mice, revealing no additional protection in these mice. Together, these results support the selectivity of ONO-8713 toward EP1 receptor and suggest the neurotoxic role of EP1 receptor. Furthermore, the EP1 receptor role in ischemic brain damage was investigated using a model of middle cerebral artery occlusion (MCAO) and reperfusion. The infarct volume was significantly reduced to 56.9 +/- 11.5% in EP1-/- mice, as compared to wildtype controls. This is the first study that demonstrates that EP1 receptor aggravates neurotoxicity and that modulation of this receptor can determine the outcomes in both excitotoxic and focal ischemic neuronal damage.

Cyclooxygenase-2 Does Not Contribute to Postischemic Production of Reactive Oxygen Species

“…We have shown here that COX-2-derived ROS do not contribute to ischemic damage. Although the data are consistent with the hypothesis that COX-2-derived prostanoids are important mediators of injury and a potential therapeutic target (Ahmad et al, 2006;Carlson, 2003;Kawano et al, 2006), we cannot rule out a pathogenic role of COX-2-derived carbon-centered radicals.…”

Elevated microsomal prostaglandin‐E synthase‐1 in Alzheimer's disease

“…For example, EP2 receptor sites, despite neuroprotective capabilities at low doses [13], have been found to create a positive feedback loop by leading to further Aβ production [8]. In astrocytes, the elevated PGE 2 might also cause glutamate excitotoxicity via stimulation of the EP1 receptor [41][42][43][44]. Interestingly, in our studies mPGES-1 appeared to be up-regulated in the pyramidal neurons in advanced AD brains.…”

Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury

“…We previously reported that in mice, the EP1 receptor plays a toxic role in transient cerebral ischemia and excitotoxicity models (Ahmad et al, 2006a), a finding further substantiated by Kawano et al (2006), and that EP2 and EP4 receptor activation is protective in N-methyl-Daspartic acid (NMDA)-induced excitotoxic lesions (Ahmad et al, 2005;Ahmad et al, 2006b). We also have evaluated the effects of the drug 1-OH-PGE1, which stimulates EP4 and to a lesser extent EP3, and found it to be neuroprotective in transient ischemia (Ahmad et al, 2006c) and oxidative stress after β-amyloid exposure in mouse primary cultured neurons (Echeverria et al, 2005).…”

“…Then the mice were mounted on a stereotactic frame and injected with 0.2 μl of different doses of ONO-AE-248 (0.5 nmol, 2.5 nmol, or 5.0 nmol) or vehicle (DMSO) via a 1-μl Hamilton syringe (Reno, NV) into the right lateral ventricle as described previously (Ahmad et al, 2006a). After the injection, the needle was retracted slowly, the hole was plugged with bone wax, and the wound was sutured.…”