Postnatal Dexamethasone Therapy and Cerebral Tissue Volumes in Extremely Low Birth Weight Infants

Parikh, Nehal A.; Lasky, Robert E.; Kennedy, Kathleen A.; Moya, Fernando; Hochhäuser, Leo; Romo, Seferino; Tyson, Jon E.

doi:10.1542/peds.2006-1354

Cited by 108 publications

(99 citation statements)

References 30 publications

(32 reference statements)

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“…Earlier studies showed that the corticosteroid dexamethasone, used mostly to prevent BPD, has a negative effect on brain growth and especially on cerebellar growth. 48 However, we did not find an independent effect of corticosteroid-treated BPD on the volume of any brain region. An explanation may be that in our institution hydrocortisone is used instead of dexamethasone.…”

Section: Discussioncontrasting

confidence: 73%

Patent Ductus Arteriosus and Brain Volume

et al. 2016

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Section: Discussioncontrasting

confidence: 73%

Patent Ductus Arteriosus and Brain Volume

et al. 2016

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“…Even multiple courses of antenatal GC treatment do not appear to confer significant neurodevelopmental risk at 2-3 years of age (45,54), although school-age follow-up studies are required to fully assess this issue. In contrast, many studies show that use of neonatal (i.e., postnatal) treatment with Dex leads to motor and intellectual deficits (3,4,6,20).…”

Section: Clinical Implications the Synthetic Gcs Dex And β-Methasonementioning

confidence: 98%

“…ous studies have indicated that GC treatment results in decreased cerebellar volumes in the rodent and human brain (19,20). To confirm the effects of GC treatment on early neonatal cerebellar development involving multiple courses, we treated C57BL/6J mouse pups with Dex daily for 1 week from P0 to P7 (Figure 1).…”

Section: Gc Treatment Inhibits Cerebellar Growth and Cgnp Proliferatimentioning

confidence: 99%

Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism

Heine¹,

Rowitch²

2009

J. Clin. Invest.

136

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Glucocorticoids (GCs) are administered to human fetuses at risk of premature delivery and to infants with life-threatening respiratory and cardiac conditions. However, there are ongoing concerns about adverse effects of GC treatment on the developing human brain, although the precise molecular mechanisms underlying GCinduced brain injury are unclear. Here, we identified what we believe to be novel cross-antagonistic interactions of Sonic hedgehog (Shh) and GC signaling in proliferating mouse cerebellar granule neuron precursors (CGNPs). Chronic GC treatment (from P0 through P7) in mouse pups inhibited Shh-induced proliferation and upregulation of expression of N-myc, Gli1, and D-type cyclin protein in CGNPs. Conversely, acute GC treatment (on P7 only) caused transient apoptosis. Shh signaling antagonized these effects of GCs, in part by induction of 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2). Importantly, 11βHSD2 antagonized the effects of the GCs corticosterone, hydrocortisone, and prednisolone, but not the synthetic GC dexamethasone. Our findings indicate that Shh signaling is protective in the setting of GC-induced mouse neonatal brain injury. Furthermore, they led us to propose that 11βHSD2-sensitive GCs (e.g., hydrocortisone) should be used in preference to dexamethasone in neonatal human infants because of the potential for reduced neurotoxicity.

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“…While the specific targets of the anti-inflammatory effects of corticosteroid treatment in the model remain undefined, infection-induced soluble inflammatory mediators, including tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), and IFN-␤, were decreased (29). Because of the potential toxicity of corticosteroids for the developing CNS, as well as the off-target effects of corticosteroids that have been documented in clinical studies and in animal models, we sought more targeted approaches to decrease CNS inflammation in infected mice (30)(31)(32). We focused our studies on responses associated with TNF-␣ because pathway analyses of the transcriptome from cerebella of infected mice revealed that TNF-␣ represented a central node in the pathway of the observed inflammatory responses (26).…”

mentioning

confidence: 99%

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Seleme

Kosmac

Jonjić³

et al. 2017

J Virol

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Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-␣)-neutralizing antibodies decreased the frequency of CD45 ϩ Ly6C hi CD11b ϩ CCR2 ϩ activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMVinfected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-␣ is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain.IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the most common viral infection of the developing human fetus and can result in neurodevelopmental sequelae. Mechanisms of disease leading to neurodevelopmental deficits in infected infants remain undefined, but postulated pathways include loss of neuronal progenitor cells, damage to the developing vascular system of the brain, and altered cellular positioning. Direct virus-mediated cytopathic effects cannot explain the phenotypes of brain damage in most infected infants. Using a mouse model that recapitulates characteristics of the brain infection described in human infants, we have shown that TNF-␣ plays a key role in brain inflammation, including recruitment of inflammatory mononuclear cells. Neutralization of TNF-␣ normalized neurodevelopmental abnormalities in infected mice, providing evidence that virus-induced inflammation is a major component of disease in the developing brain. These results suggest that interventions limiting inflammation associated with the infection could potentially improve the neurologic outcome of infants infected in utero with HCMV.

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Postnatal Dexamethasone Therapy and Cerebral Tissue Volumes in Extremely Low Birth Weight Infants

Cited by 108 publications

References 30 publications

Patent Ductus Arteriosus and Brain Volume

Patent Ductus Arteriosus and Brain Volume

Hedgehog signaling has a protective effect in glucocorticoid-induced mouse neonatal brain injury through an 11βHSD2-dependent mechanism

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

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