title: Hyaluronidase and Hyaluronan Oligosaccharides Promote Neurological Recovery after Intraventricular Hemorrhage.
abstract: Intraventricular hemorrhage (IVH) in premature infants results in inflammation, arrested oligodendrocyte progenitor cell (OPC) maturation, and reduced myelination of the white matter. Hyaluronan (HA) inhibits OPC maturation and complexes with the heavy chain (HC) of glycoprotein inter-α-inhibitor to form pathological HA (HC-HA complex), which exacerbates inflammation. Therefore, we hypothesized that IVH would result in accumulation of HA, and that either degradation of HA by hyaluronidase treatment or elimination of HCs from pathological HA by HA oligosaccharide administration would restore OPC maturation, myelination, and neurological function in survivors with IVH. To test these hypotheses, we used the preterm rabbit model of glycerol-induced IVH and analyzed autopsy samples from premature infants. We found that total HA levels were comparable in both preterm rabbit pups and human infants with and without IVH, but HA receptors--CD44, TLR2, TLR4--were elevated in the forebrain of both humans and rabbits with IVH. Hyaluronidase treatment of rabbits with IVH reduced CD44 and TLR4 expression, proinflammatory cytokine levels, and microglia infiltration. It also promoted OPC maturation, myelination, and neurological recovery. HC-HA and tumor necrosis factor-stimulated gene-6 were elevated in newborns with IVH; and depletion of HC-HA levels by HA oligosaccharide treatment reduced inflammation and enhanced myelination and neurological recovery in rabbits with IVH. Hence, hyaluronidase or HA oligosaccharide treatment represses inflammation, promotes OPC maturation, and restores myelination and neurological function in rabbits with IVH. These therapeutic strategies might improve the neurological outcome of premature infants with IVH. Significance statement: Approximately 12,000 premature infants develop IVH every year in the United States, and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The onset of IVH induces inflammation of the periventricular white matter, which results in arrested maturation of OPCs and myelination failure. HA is a major component of the extracellular matrix of the brain, which regulates inflammation through CD44 and TLR2/4 receptors. Here, we show two mechanism-based strategies that effectively enhanced myelination and neurological recovery in preterm rabbit model of IVH. First, degrading HA by hyaluronidase treatment reduced CD44 and TLR4 expression, proinflammatory cytokines, and microglial infiltration, as well as promoted oligodendrocyte maturation and myelination. Second, intraventricular injection of HA oligosaccharide reduced inflammation and enhanced myelination, conceivably by depleting HC-HA levels.
authors.affiliation: Departments of Pediatrics and.
authors.forename: Govindaiah
authors.initials: G
authors.lastname: Vinukonda
authors.affiliation: Departments of Pediatrics and.
authors.forename: Preeti
authors.initials: P
authors.lastname: Dohare
authors.affiliation: Departments of Pediatrics and.
authors.forename: Arslan
authors.identifier: 0000-0002-4771-7995
authors.initials: A
authors.lastname: Arshad
authors.affiliation: Departments of Pediatrics and.
authors.forename: Muhammad T
authors.initials: MT
authors.lastname: Zia
authors.affiliation: Departments of Pediatrics and.
authors.forename: Sanjeet
authors.initials: S
authors.lastname: Panda
authors.affiliation: Departments of Pediatrics and.
authors.forename: Ritesh
authors.initials: R
authors.lastname: Korumilli
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97239, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Kayton
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Vincent C
authors.initials: VC
authors.lastname: Hascall
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lauer
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; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002552:Cerebral Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000096:biosynthesis*; D006821:Hyaluronoglucosaminidase / Q000096:biosynthesis*; D007231:Infant, Newborn; D007276:Injections, Intraventricular; D008297:Male; D009844:Oligosaccharides / Q000008:administration & dosage / Q000096:biosynthesis*; D011247:Pregnancy; D011817:Rabbits; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*
chemical_list: D009844:Oligosaccharides; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase
keywords: hyaluronan; hyaluronan oligosaccharides; hyaluronidase; microglia; myelination; oligodendrocyte