title: Treatment with thyroxine restores myelination and clinical recovery after intraventricular hemorrhage.
abstract: Intraventricular hemorrhage (IVH) remains a major cause of white matter injury in preterm infants with no viable therapeutic strategy to restore myelination. Maturation of oligodendrocytes and myelination is influenced by thyroid hormone (TH) signaling, which is mediated by TH receptor α (TRα) and TRβ. In the brain, cellular levels of TH are regulated by deiodinases, with deiodinase-2 mediating TH activation and deiodinase-3 TH inactivation. Therefore, we hypothesized that IVH would decrease TH signaling via changes in the expression of deiodinases and/or TRs, and normalization of TH signaling would enhance maturation of oligodendrocytes and myelination in preterm infants with IVH. These hypotheses were tested using both autopsy materials from human preterm infants and a rabbit model of IVH. We found that deiodinase-2 levels were reduced, whereas deiodinase-3 levels were increased in brain samples of both humans and rabbits with IVH compared with controls without IVH. TRα expression was also increased in human infants with IVH. Importantly, treatment with TH accelerated the proliferation and maturation of oligodendrocytes, increased transcription of Olig2 and Sox10 genes, augmented myelination, and restored neurological function in pups with IVH. Consistent with these findings, the density of myelinating oligodendrocytes was almost doubled in TH-treated human preterm infants compared with controls. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TRα. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH.
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, Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97239, Department of Neuroscience, University of Connecticut, Farmington, Connecticut 06269, and Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida 33146.
authors.forename: Linnea R
authors.initials: LR
authors.lastname: Vose
authors.forename: Govindaiah
authors.initials: G
authors.lastname: Vinukonda
authors.forename: Sungro
authors.initials: S
authors.lastname: Jo
authors.forename: Omid
authors.initials: O
authors.lastname: Miry
authors.forename: Daniel
authors.initials: D
authors.lastname: Diamond
authors.forename: Ritesh
authors.initials: R
authors.lastname: Korumilli
authors.forename: Arslan
authors.initials: A
authors.lastname: Arshad
authors.forename: Muhammad T K
authors.initials: MT
authors.lastname: Zia
authors.forename: Furong
authors.initials: F
authors.lastname: Hu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kayton
authors.forename: Edmund F
authors.initials: EF
authors.lastname: La Gamma
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bansal
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Bianco
authors.forename: Praveen
authors.initials: P
authors.lastname: Ballabh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000503:physiopathology*; D002552:Cerebral Ventricles / Q000502:physiology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D011817:Rabbits; D020127:Recovery of Function / Q000502:physiology*; D013974:Thyroxine / Q000502:physiology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D013974:Thyroxine