RESUMO
Synthetic glucocorticoids (sGCs) such as dexamethasone (DEX), while used to mitigate inflammation and disease progression in premature infants with severe bronchopulmonary dysplasia (BPD), are also associated with significant adverse neurologic effects such as reductions in myelination and abnormalities in neuroanatomical development. Ciclesonide (CIC) is a sGC prodrug approved for asthma treatment that exhibits limited systemic side effects. Carboxylesterases enriched in the lower airways convert CIC to the glucocorticoid receptor (GR) agonist des-CIC. We therefore examined whether CIC would likewise activate GR in neonatal lung but have limited adverse extra-pulmonary effects, particularly in the developing brain. Neonatal rats were administered subcutaneous injections of CIC, DEX or vehicle from postnatal days 1-5 (PND1-PND5). Systemic effects linked to DEX exposure, including reduced body and brain weight, were not observed in CIC treated neonates. Furthermore, CIC did not trigger the long-lasting reduction in myelin basic protein expression in the cerebral cortex nor cerebellar size caused by neonatal DEX exposure. Conversely, DEX and CIC were both effective at inducing the expression of select GR target genes in neonatal lung, including those implicated in lung-protective and anti-inflammatory effects. Thus, CIC is a promising, novel candidate drug to treat or prevent BPD in neonates given its activation of GR in neonatal lung and limited adverse neurodevelopmental effects. Furthermore, since sGCs such as DEX administered to pregnant women in pre-term labor can adversely affect fetal brain development, the neurological-sparing properties of CIC, make it an attractive alternative for DEX to treat pregnant women severely ill with respiratory illness, such as with asthma exacerbations or COVID-19 infections.
Assuntos
Cerebelo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Glucocorticoides , Pulmão/efeitos dos fármacos , Pregnenodionas/farmacologia , Pró-Fármacos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Anti-Inflamatórios/farmacologia , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Dexametasona/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Básica da Mielina/biossíntese , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores de Glucocorticoides/efeitos dos fármacos , Tratamento Farmacológico da COVID-19RESUMO
Prenatal exposure to synthetic glucocorticoids (sGCs) reprograms brain development and predisposes the developing fetus towards potential adverse neurodevelopmental outcomes. Using a mouse model of sGC administration, previous studies show that these changes are accompanied by sexually dimorphic alterations in the transcriptome of neural stem and progenitor cells (NSPCs) derived from the embryonic telencephalon. Because cell type-specific gene expression profiles tightly regulate cell fate decisions and are controlled by a flexible landscape of chromatin domains upon which transcription factors and enhancer elements act, we multiplexed data from four genome-wide assays: RNA-seq, ATAC-seq (assay for transposase accessible chromatin followed by genome wide sequencing), dual cross-linking ChIP-seq (chromatin immunoprecipitation followed by genome wide sequencing), and microarray gene expression to identify novel relationships between gene regulation, chromatin structure, and genomic glucocorticoid receptor (GR) action in NSPCs. These data reveal that GR binds preferentially to predetermined regions of accessible chromatin to influence gene programming and cell fate decisions. In addition, we identify SOX2 as a transcription factor that impacts the genomic response of select GR target genes to sGCs (i.e., dexamethasone) in NSPCs.
Assuntos
Glucocorticoides , Células-Tronco Neurais , Feminino , Gravidez , Cromatina/metabolismo , Regulação da Expressão Gênica , Genômica , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Células-Tronco Neurais/metabolismo , Receptores de Glucocorticoides/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Camundongos , Células-Tronco Embrionárias MurinasRESUMO
Fetal exposure to synthetic glucocorticoids reprograms distinct neural circuits in the developing brain, often in a sex-specific manner, via mechanisms that remain poorly understood. To reveal whether such reprogramming is associated with select molecular signatures, we characterized the transcriptome of primary, embryonic mouse cerebral cortical and hypothalamic neural progenitor/stem cells derived from individual male and female embryos exposed to the synthetic glucocorticoid, dexamethasone. Gene expression profiling by RNA-Seq identified differential expression of common and unique genes based upon brain region, sex, and/or dexamethasone exposure. These gene expression datasets provide a unique resource that will inform future studies examining the molecular mechanisms responsible for region- and sex-specific reprogramming of the fetal brain brought about by in utero exposure to excess glucocorticoids.
Assuntos
Córtex Cerebral/embriologia , Dexametasona/farmacologia , Embrião de Mamíferos/citologia , Hipotálamo/embriologia , Células-Tronco Neurais/metabolismo , Caracteres Sexuais , Transcriptoma/genética , Animais , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Transcriptoma/efeitos dos fármacosRESUMO
Glucocorticoids (GCs) regulate distinct physiological processes in the developing fetus, in particular accelerating organ maturation that enables the fetus to survive outside the womb. In preterm birth, the developing fetus does not receive sufficient exposure to endogenous GCs in utero for proper organ development predisposing the neonate to complications including intraventricular hemorrhage, respiratory distress syndrome (RDS) and necrotizing enterocolitis (NEC). Synthetic GCs (sGCs) have proven useful in the prevention of these complications since they are able to promote the rapid maturation of underdeveloped organs present in the fetus. While these drugs have proven to be clinically effective in the prevention of IVH, RDS and NEC, they may also trigger adverse developmental side effects. This review will examine the current clinical use of antenatal sGC therapy in preterm birth, their placental metabolism, and their effects on the developing brain.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Glucocorticoides/uso terapêutico , Animais , Feminino , Humanos , Recém-Nascido , Gravidez , Nascimento Prematuro/tratamento farmacológico , Cuidado Pré-NatalRESUMO
The 22q11 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans and one of the chromosomal conditions most associated with psychosis and autism spectrum disorder. To date, only 2 neuropathologic studies of 22q11DS have been reported. Findings included polymicrogyria, neuronal heterotopias, excess subcortical white-matter (interstitial) neurons, significant white-matter gliosis/hypomyelination, and microvasculopathy. Here, we report on a 3-month-old infant with documented 22q11DS, tetralogy of Fallot, and pulmonary atresia. The brain exhibited tortuous cerebral vessels and proportionately smaller occipital lobes. Histologic examination revealed cerebral white-matter pathology and subtle differences in cortical lamination, including an excess of interstitial white-matter neurons compared with a sample of age-matched controls. There was a 15% increase in DARPP-32+ medium spiny neurons in the anterior-superior caudate. In this first neuropathologic report of an infant with 22q11DS, the findings were similar to previously reported manifestations and are likely secondary to perfusion issues, developmental microvasculopathy, and abnormal frontal cortical development.