Stimulation of prostaglandin E2-EP3 receptors exacerbates stroke and excitotoxic injury.
The effect of PGE(2) EP3 receptors on injury size was investigated following cerebral ischemia and induced excitotoxicity in mice. Treatment with the selective EP3 agonist ONO-AE-248 significantly and dose-dependently increased infarct size in the middle cerebral artery occlusion model. In a separate experiment, pretreatment with ONO-AE-248 exacerbated the lesion caused by N-methyl-d-aspartic acid-induced acute excitotoxicity. Conversely, genetic deletion of EP3 provided protection against N-methyl-d-aspartic acid-induced toxicity. The results suggest that PGE(2), by stimulating EP3 receptors, can contribute to the toxicity associated with cyclooxygenase and that antagonizing this receptor could be used therapeutically to protect against stroke- and excitotoxicity-induced brain damage.
Ahmad
Muzamil
M
Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Ahmad
Abdullah Shafique
AS
Zhuang
Hean
H
Maruyama
Takayuki
T
Narumiya
Shuh
S
Doré
Sylvain
S
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D001930:Brain Injuries / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D015232:Dinoprostone / Q000009:adverse effects / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016202:N-Methylaspartate; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D058308:Receptors, Prostaglandin E, EP3 Subtype
C121546:ONO AE 248; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D016202:N-Methylaspartate; D015232:Dinoprostone