title: PAR-1, -4, and the mTOR Pathway Following Germinal Matrix Hemorrhage.
abstract: Germinal matrix hemorrhage (GMH) is the most common cause of neurological complications of prematurity and has lasting implications. PAR-1 and PAR-4 receptors are involved with upstream signaling pathways following brain hemorrhage in adult models of stroke, of which the mammalian target of rapamycin (mTOR) is a potential downstream mediator. Therefore, we hypothesized a role for PAR-1, -4/ mTOR signaling following GMH brain injury. Postnatal day 7 Sprague-Dawley rats were subjected to GMH through stereotactic infusion of collagenase into the right ganglionic eminence. Rodents were euthanized at 72 h (short term), or 4 weeks (long term). Short-term mTOR expression was evaluated by Western blot in the context of PAR-1 (SCH-79797) and PAR-4 (P4pal10) inhibition. Pups in the long-term group were administered the selective mTOR inhibitor (rapamycin) with neurobehavioral and brain pathological examinations performed at 4 weeks. Pharmacological PAR-1, -4 antagonism normalized the increased mTOR expression following GMH. Early inhibition of mTOR by rapamycin improved long-term outcomes in rats. Mammalian-TOR signaling plays an important role in brain injury following neonatal GMH, possibly involving upstream PAR-1, -4 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: Jerry
authors.initials: J
authors.lastname: Flores
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: 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* / Q000378:metabolism / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; 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*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D010975:Platelet Aggregation Inhibitors
chemical_list: D007166:Immunosuppressive Agents; 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; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D013917:Thrombin; C112908:protease-activated receptor 4; D020123:Sirolimus; D010975:Platelet Aggregation Inhibitors
keywords: Germinal matrix hemorrhage; Hydrocephalus; Neonatal rats; Neurological dysfunction; Stroke, experimental