title: Therapeutic window for cyclooxygenase-2 related anti-inflammatory therapy after status epilepticus.
abstract: As a prominent inflammatory effector of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) mediates brain inflammation and injury in many chronic central nervous system (CNS) conditions including seizures and epilepsy, largely through its receptor subtype EP2. However, EP2 receptor activation might also be neuroprotective in models of excitotoxicity and ischemia. These seemingly incongruent observations expose the delicacy of immune and inflammatory signaling in the brain; thus the therapeutic window for quelling neuroinflammation might vary with injury type and target molecule. Here, we identify a therapeutic window for EP2 antagonism to reduce delayed mortality and functional morbidity after status epilepticus (SE) in mice. Importantly, treatment must be delayed relative to SE onset to be effective, a finding that could be explained by the time-course of COX-2 induction after SE and compound pharmacokinetics. A large number of inflammatory mediators were upregulated in hippocampus after SE with COX-2 and IL-1β temporally leading many others. Thus, EP2 antagonism represents a novel anti-inflammatory strategy to treat SE with a tightly-regulated therapeutic window.
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA 30322, United States; Division of Pharmaceutical sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, United States. Electronic address: jianxiong.jiang@uc.edu.
authors.forename: Jianxiong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA 30322, United States.
authors.forename: Myung-Soon
authors.initials: MS
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA 30322, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Quan
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA 30322, United States.
authors.forename: Paoula
authors.initials: P
authors.lastname: Gueorguieva
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA 30322, United States.
authors.forename: Thota
authors.initials: T
authors.lastname: Ganesh
authors.affiliation: Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA 30322, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Dingledine
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D010862:Pilocarpine; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013226:Status Epilepticus / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality
chemical_list: D000893:Anti-Inflammatory Agents; D007211:Indoles; D058307:Receptors, Prostaglandin E, EP2 Subtype; C000603409:TG6-10-1; D010862:Pilocarpine; D051546:Cyclooxygenase 2
keywords: Chemokine; Cyclooxygenase; Cytokine; EP2; Epilepsy; Gliosis; Interleukin-1β; Neuroinflammation; Prostaglandin; Seizure; Status epilepticus