Treatment with thyroxine restores myelination and clinical recovery after intraventricular hemorrhage

Linnea R. Vose, Govindaiah Vinukonda, Sungro Jo, Omid Miry, Daniel Diamond, Ritesh Korumilli, Arslan Arshad, Muhammad T K Zia, Furong Hu, Robert J. Kayton, Edmund F. La Gamma, Rashmi Bansal, Antonio C. Bianco, Praveen Ballabh

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)17232-17246
Number of pages15
JournalJournal of Neuroscience
Volume33
Issue number44
DOIs
StatePublished - 2013
Externally publishedYes

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Thyroxine
Thyroid Hormones
Iodide Peroxidase
Hemorrhage
Premature Infants
Oligodendroglia
Therapeutics
Rabbits
Thyroid Hormone Receptors
Brain
Autopsy
Wounds and Injuries

ASJC Scopus subject areas

  • Neuroscience(all)

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Treatment with thyroxine restores myelination and clinical recovery after intraventricular hemorrhage. / Vose, Linnea R.; Vinukonda, Govindaiah; Jo, Sungro; Miry, Omid; Diamond, Daniel; Korumilli, Ritesh; Arshad, Arslan; Zia, Muhammad T K; Hu, Furong; Kayton, Robert J.; La Gamma, Edmund F.; Bansal, Rashmi; Bianco, Antonio C.; Ballabh, Praveen.

In: Journal of Neuroscience, Vol. 33, No. 44, 2013, p. 17232-17246.

Research output: Contribution to journalArticle

Vose, LR, Vinukonda, G, Jo, S, Miry, O, Diamond, D, Korumilli, R, Arshad, A, Zia, MTK, Hu, F, Kayton, RJ, La Gamma, EF, Bansal, R, Bianco, AC & Ballabh, P 2013, 'Treatment with thyroxine restores myelination and clinical recovery after intraventricular hemorrhage', Journal of Neuroscience, vol. 33, no. 44, pp. 17232-17246. https://doi.org/10.1523/JNEUROSCI.2713-13.2013
Vose, Linnea R. ; Vinukonda, Govindaiah ; Jo, Sungro ; Miry, Omid ; Diamond, Daniel ; Korumilli, Ritesh ; Arshad, Arslan ; Zia, Muhammad T K ; Hu, Furong ; Kayton, Robert J. ; La Gamma, Edmund F. ; Bansal, Rashmi ; Bianco, Antonio C. ; Ballabh, Praveen. / Treatment with thyroxine restores myelination and clinical recovery after intraventricular hemorrhage. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 44. pp. 17232-17246.
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AU - Vose, Linnea R.

AU - Vinukonda, Govindaiah

AU - Jo, Sungro

AU - Miry, Omid

AU - Diamond, Daniel

AU - Korumilli, Ritesh

AU - Arshad, Arslan

AU - Zia, Muhammad T K

AU - Hu, Furong

AU - Kayton, Robert J.

AU - La Gamma, Edmund F.

AU - Bansal, Rashmi

AU - Bianco, Antonio C.

AU - Ballabh, Praveen

PY - 2013

Y1 - 2013

N2 - 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.

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