title: AMPA-Kainate Receptor Inhibition Promotes Neurologic Recovery in Premature Rabbits with Intraventricular Hemorrhage.
abstract: Intraventricular hemorrhage (IVH) in preterm infants leads to cerebral inflammation, reduced myelination of the white matter, and neurological deficits. No therapeutic strategy exists against the IVH-induced white matter injury. AMPA-kainate receptor induced excitotoxicity contributes to oligodendrocyte precursor cell (OPC) damage and hypomyelination in both neonatal and adult models of brain injury. Here, we hypothesized that IVH damages white matter via AMPA receptor activation, and that AMPA-kainate receptor inhibition suppresses inflammation and restores OPC maturation, myelination, and neurologic recovery in preterm newborns with IVH. We tested these hypotheses in a rabbit model of glycerol-induced IVH and evaluated the expression of AMPA receptors in autopsy samples from human preterm infants. GluR1-GluR4 expressions were comparable between preterm humans and rabbits with and without IVH. However, GluR1 and GluR2 levels were significantly lower in the embryonic white matter and germinal matrix relative to the neocortex in both infants with and without IVH. Pharmacological blockade of AMPA-kainate receptors with systemic NBQX, or selective AMPA receptor inhibition by intramuscular perampanel restored myelination and neurologic recovery in rabbits with IVH. NBQX administration also reduced the population of apoptotic OPCs, levels of several cytokines (TNFα, IL-β, IL-6, LIF), and the density of Iba1(+) microglia in pups with IVH. Additionally, NBQX treatment inhibited STAT-3 phosphorylation, but not astrogliosis or transcription factors regulating gliosis. Our data suggest that AMPA-kainate receptor inhibition alleviates OPC loss and IVH-induced inflammation and restores myelination and neurologic recovery in preterm rabbits with IVH. Therapeutic use of FDA-approved perampanel treatment might enhance neurologic outcome in premature infants with IVH.
  
  
  CONCLUSIONS
  Intraventricular hemorrhage (IVH) is a major complication of prematurity and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The development of IVH leads to inflammation of the periventricular white matter, apoptosis and arrested maturation of oligodendrocyte precursor cells, and hypomyelination. Here, we show that AMPA-kainate receptor inhibition by NBQX suppresses inflammation, attenuates apoptosis of oligodendrocyte precursor cells, and promotes myelination as well as clinical recovery in preterm rabbits with IVH. Importantly, AMPA-specific inhibition by the FDA-approved perampanel, which unlike NBQX has a low side-effect profile, also enhances myelination and neurological recovery in rabbits with IVH. Hence, the present study highlights the role of AMPA-kainate receptor in IVH-induced white matter injury and identifies a novel strategy of neuroprotection, which might improve the neurological outcome for premature infants with IVH.
authors.affiliation: Departments of Pediatrics and.
authors.forename: Preeti
authors.initials: P
authors.lastname: Dohare
authors.affiliation: Departments of Pediatrics and Cell Biology and Anatomy, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York 10595.
authors.forename: Muhammad T
authors.initials: MT
authors.lastname: Zia
authors.affiliation: Departments of Pediatrics and.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Ahmed
authors.affiliation: Departments of Pediatrics and.
authors.forename: Asad
authors.initials: A
authors.lastname: Ahmed
authors.affiliation: Departments of Pediatrics and.
authors.forename: Vivek
authors.initials: V
authors.lastname: Yadala
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12208.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Schober
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030.
authors.forename: Juan Alberto
authors.initials: JA
authors.lastname: Ortega
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Kayton
authors.affiliation: Reynolds Oklahoma Center on Aging, and Department of Geriatric Medicine, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Ungvari
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York 12208.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Mongin
authors.affiliation: Departments of Pediatrics and Cell Biology and Anatomy, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York 10595, Pballabh@msn.com.
authors.forename: Praveen
authors.initials: P
authors.lastname: Ballabh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D020013:Calcium Signaling / Q000187:drug effects; D002552:Cerebral Ventricles / Q000503:physiopathology / Q000648:ultrastructure; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005990:Glycerol / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D006801:Humans; D056784:Leukoencephalopathies / Q000188:drug therapy / Q000209:etiology; D008297:Male; D009422:Nervous System Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D009570:Nitriles; D011247:Pregnancy; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use; D011810:Quinoxalines / Q000494:pharmacology / Q000627:therapeutic use; D011817:Rabbits; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*
chemical_list: D016207:Cytokines; D018691:Excitatory Amino Acid Antagonists; D009570:Nitriles; D011728:Pyridones; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C551441:perampanel; D005990:Glycerol
keywords: AMPA; NBQX; myelination; oligodendrocyte; perampanel