title: Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation.
abstract: Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood-brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.
authors: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA. jjiang3@emory.edu
authors: Jianxiong
authors: J
authors: Jiang
authors: Yi
authors: Y
authors: Quan
authors: Thota
authors: T
authors: Ganesh
authors: Wendy A
authors: WA
authors: Pouliot
authors: F Edward
authors: FE
authors: Dudek
authors: Raymond
authors: R
authors: Dingledine
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008959:Models, Neurological; D009410:Nerve Degeneration / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D010862:Pilocarpine; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D013226:Status Epilepticus / Q000150:complications / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D016019:Survival Analysis; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000927:Anticonvulsants; D007211:Indoles; D058307:Receptors, Prostaglandin E, EP2 Subtype; D010862:Pilocarpine
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