title: Cyclooxygenase-2 Inhibition Provides Lasting Protection Following Germinal Matrix Hemorrhage in Premature Infant Rats.
abstract: Germinal matrix hemorrhage (GMH) is a major cause of brain damage in prematurity and has long-lasting neurological implications. The development of brain inflammation contributes to brain injury, leading to a lifetime of neurologic deficits. PAR-1 and 4 receptors are involved with inflammatory pathways after brain hemorrhage in adult models of stroke, of which cyclooxygenase-2 (COX-2) is a potential mediator. We therefore hypothesized a role for PAR-1, 4/ COX-2 signaling following GMH. Postnatal day 7 Sprague-Dawley rats were subjected to GMH induction, which entailed stereotactic collagenase infusion into the ganglionic eminence. Animals were euthanized at two time points: 72 h (short-term) or 4 weeks (long-term). Short-term COX-2 expression was evaluated in the context of PAR-1 (SCH-79797) and PAR-4 (P4pal10) inhibition. Pups in the long-term group were administered the selective COX-2 inhibitor (NS-398); and the neurobehavioral and pathological examinations were performed 4 weeks later. Pharmacological PAR-1, 4 antagonism normalized COX-2 expression following GMH and reduced hydrocephalus. Early inhibition of COX-2 by NS-398 improved long-term neurobehavioral outcomes. COX-2 signaling plays an important role in brain injury following neonatal GMH, possibly through upstream PAR-1, 4 receptor mechanisms.
authors.affiliation: Division of Physiology and Pharmacology, School of Medicine, Loma Linda, CA, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Lekic
authors.affiliation: Division of Physiology and Pharmacology, School of Medicine, Loma Linda, CA, USA.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Krafft
authors.affiliation: Division of Physiology and Pharmacology, School of Medicine, Loma Linda, CA, USA.
authors.forename: Damon
authors.initials: D
authors.lastname: Klebe
authors.affiliation: Division of Physiology and Pharmacology, School of Medicine, Loma Linda, CA, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Rolland
authors.affiliation: Division of Physiology and Pharmacology, School of Medicine, Loma Linda, CA, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Flores
authors.affiliation: Division of Physiology and Pharmacology, School of Medicine, Loma Linda, CA, USA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.affiliation: Division of Physiology and Pharmacology, School of Medicine, Loma Linda, CA, USA. johnzhang3910@yahoo.com.|Department of Neurosurgery, School of Medicine, Loma Linda, CA, USA. johnzhang3910@yahoo.com.|Department of Physiology and Pharmacology, Loma Linda University School of Medicine, 11041 Campus Street, Risley Hall Rm 219, Loma Linda, CA, 92354, USA. johnzhang3910@yahoo.com.
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D020300:Intracranial Hemorrhages / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009842:Oligopeptides / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors; D010975:Platelet Aggregation Inhibitors
chemical_list: C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D009842:Oligopeptides; D011758:Pyrroles; D011799:Quinazolines; D018179:Receptors, Thrombin; C524864:palmitoyl-seryl-glycyl-arginyl-arginyl-tyrosyl-glycyl-histidyl-alanyl-leucyl-arginine; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; C112908:protease-activated receptor 4; D010975:Platelet Aggregation Inhibitors
keywords: COX-2; Germinal matrix hemorrhage; Hydrocephalus; Neonatal rats; Neurological dysfunction; Stroke, experimental