AMPA-kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage

Preeti Dohare, Muhammad T. Zia, Ehsan Ahmed, Asad Ahmed, Vivek Yadala, Alexandra L. Schober, Juan Alberto Ortega, Robert Kayton, Zoltan Ungvari, Alexander A. Mongin, Praveen Ballabh

Research output: Contribution to journalArticle

12 Citations (Scopus)

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-α 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.

Original languageEnglish (US)
Pages (from-to)3363-3377
Number of pages15
JournalJournal of Neuroscience
Volume36
Issue number11
DOIs
StatePublished - Mar 16 2016
Externally publishedYes

Fingerprint

Kainic Acid Receptors
AMPA Receptors
Nervous System
Hemorrhage
Rabbits
Oligodendroglia
Premature Infants
Inflammation
Gliosis
Neocortex
Microglia
Therapeutic Uses
Glycerol
Brain Injuries
Autopsy
Interleukin-6
Transcription Factors

Keywords

  • AMPA
  • Myelination
  • NBQX
  • Oligodendrocyte
  • Perampanel

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

AMPA-kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage. / Dohare, Preeti; Zia, Muhammad T.; Ahmed, Ehsan; Ahmed, Asad; Yadala, Vivek; Schober, Alexandra L.; Ortega, Juan Alberto; Kayton, Robert; Ungvari, Zoltan; Mongin, Alexander A.; Ballabh, Praveen.

In: Journal of Neuroscience, Vol. 36, No. 11, 16.03.2016, p. 3363-3377.

Research output: Contribution to journalArticle

Dohare, P, Zia, MT, Ahmed, E, Ahmed, A, Yadala, V, Schober, AL, Ortega, JA, Kayton, R, Ungvari, Z, Mongin, AA & Ballabh, P 2016, 'AMPA-kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage', Journal of Neuroscience, vol. 36, no. 11, pp. 3363-3377. https://doi.org/10.1523/JNEUROSCI.4329-15.2016
Dohare, Preeti ; Zia, Muhammad T. ; Ahmed, Ehsan ; Ahmed, Asad ; Yadala, Vivek ; Schober, Alexandra L. ; Ortega, Juan Alberto ; Kayton, Robert ; Ungvari, Zoltan ; Mongin, Alexander A. ; Ballabh, Praveen. / AMPA-kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 11. pp. 3363-3377.
@article{d6837ee1b9e745898ae810cdc58a2f92,
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-α 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.",
keywords = "AMPA, Myelination, NBQX, Oligodendrocyte, Perampanel",
author = "Preeti Dohare and Zia, {Muhammad T.} and Ehsan Ahmed and Asad Ahmed and Vivek Yadala and Schober, {Alexandra L.} and Ortega, {Juan Alberto} and Robert Kayton and Zoltan Ungvari and Mongin, {Alexander A.} and Praveen Ballabh",
year = "2016",
month = "3",
day = "16",
doi = "10.1523/JNEUROSCI.4329-15.2016",
language = "English (US)",
volume = "36",
pages = "3363--3377",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "11",

}

TY - JOUR

T1 - AMPA-kainate receptor inhibition promotes neurologic recovery in premature rabbits with intraventricular hemorrhage

AU - Dohare, Preeti

AU - Zia, Muhammad T.

AU - Ahmed, Ehsan

AU - Ahmed, Asad

AU - Yadala, Vivek

AU - Schober, Alexandra L.

AU - Ortega, Juan Alberto

AU - Kayton, Robert

AU - Ungvari, Zoltan

AU - Mongin, Alexander A.

AU - Ballabh, Praveen

PY - 2016/3/16

Y1 - 2016/3/16

N2 - 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-α 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.

AB - 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-α 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.

KW - AMPA

KW - Myelination

KW - NBQX

KW - Oligodendrocyte

KW - Perampanel

UR - http://www.scopus.com/inward/record.url?scp=84961262500&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961262500&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.4329-15.2016

DO - 10.1523/JNEUROSCI.4329-15.2016

M3 - Article

VL - 36

SP - 3363

EP - 3377

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 11

ER -