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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 ? (TR?) and TR?. 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. TR? 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 TR?. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH.

SUBMITTER: Vose LR

PROVIDER: S-EPMC3812500 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Treatment with thyroxine restores myelination and clinical recovery after intraventricular hemorrhage.

Vose Linnea R LR Vinukonda Govindaiah G Jo Sungro S Miry Omid O Diamond Daniel D Korumilli Ritesh R Arshad Arslan A Zia Muhammad T K MT Hu Furong F Kayton Robert J RJ La Gamma Edmund F EF Bansal Rashmi R Bianco Antonio C AC Ballabh Praveen P

The Journal of neuroscience : the official journal of the Society for Neuroscience 20131001 44

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 ...[more]

PMID: 24174657

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Project description: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.

Project description:Germinal matrix-intraventricular hemorrhage (GM-IVH) is the most frequent intracranial hemorrhage in the preterm infant (PT). Long-term GM-IVH-associated sequelae include cerebral palsy, sensory and motor impairment, learning disabilities, or neuropsychiatric disorders. The societal and health burden associated with GM-IVH is worsened by the fact that there is no successful treatment to limit or reduce brain damage and neurodevelopment disabilities. Caffeine (Caf) is a methylxanthine that binds to adenosine receptors, regularly used to treat the apnea of prematurity. While previous studies support the beneficial effects at the brain level of Caf in PT, there are no studies that specifically focus on the role of Caf in GM-IVH. Therefore, to further understand the role of Caf in GM-IVH, we have analyzed two doses of Caf (10 and 20 mg/kg) in a murine model of the disease. We have analyzed the short (P14) and long (P70) effects of the treatment on brain atrophy and neuron wellbeing, including density, curvature, and phospho-tau/total tau ratio. We have analyzed proliferation and neurogenesis, as well as microglia and hemorrhage burdens. We have also assessed the long-term effects of Caf treatment at cognitive level. To induce GM-IVH, we have administered intraventricular collagenase to P7 CD1 mice and have analyzed these animals in the short (P14) and long (P70) term. Caf showed a general neuroprotective effect in our model of GM-IVH of the PT. In our study, Caf administration diminishes brain atrophy and ventricle enlargement. Likewise, Caf limits neuronal damage, including neurite curvature and tau phosphorylation. It also contributes to maintaining neurogenesis in the subventricular zone, a neurogenic niche that is severely affected after GM-IVH. Furthermore, Caf ameliorates small vessel bleeding and inflammation in both the cortex and the subventricular zone. Observed mitigation of brain pathological features commonly associated with GM-IVH also results in a significant improvement of learning and memory abilities in the long term. Altogether, our data support the promising effects of Caf to reduce central nervous system complications associated with GM-IVH.

Project description:BackgroundThe presence of traumatic intraventricular hemorrhage (tIVH) following traumatic brain injury (TBI) is associated with worse neurological outcome. The mechanisms by which patients with tIVH have worse outcome are not fully understood and research is ongoing, but foundational studies that explore prognostic factors within tIVH populations are also lacking. This study aimed to further identify and characterize demographic and clinical variables within a subset of patients with TBI and tIVH that may be implicated in tIVH outcome.MethodsIn this observational study, we reviewed a large prospective TBI database to determine variables present on admission that predicted neurological outcome 6 months after injury. A review of 7,129 patients revealed 211 patients with tIVH on admission and 6-month outcome data. Hypothesized risk factors were tested in univariate analyses with significant variables (p < 0.05) included in logistic and linear regression models. Following the addition of either the Rotterdam computed tomography or Glasgow Coma Scale (GCS) score, we employed a backward selection process to determine significant variables in each multivariate model.ResultsOur study found that that hypotension (odds ratio [OR] = 0.35, 95% confidence interval [CI] = 0.13-0.94, p = 0.04) and the hemoglobin level (OR = 1.33, 95% CI = 1.09-1.63, p = 0.006) were significant predictors in the Rotterdam model, whereas only the hemoglobin level (OR = 1.29, 95% CI = 1.06-1.56, p = 0.01) was a significant predictor in the GCS model.ConclusionsThis study represents one of the largest investigations into prognostic factors for patients with tIVH and demonstrates that admission hemoglobin level and hypotension are associated with outcomes in this patient population. These findings add value to established prognostic scales, could inform future predictive modeling studies, and may provide potential direction in early medical management of patients with tIVH.

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Treatment with thyroxine restores myelination and clinical recovery after intraventricular hemorrhage.

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Treatment with thyroxine restores myelination and clinical recovery after intraventricular hemorrhage.

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