4.7 Article

Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum

期刊

NEUROBIOLOGY OF DISEASE
卷 156, 期 -, 页码 -

出版社

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2021.105422

关键词

Ciclesonide; Dexamethasone; Bronchopulmonary dysplasia; Glucocorticoids

资金

  1. National Institutes of Health [R01 HD087288, R21 HD097694, R01 HL128374, K12 HD052892]
  2. MageeWomen's Research Institute Clinical Trainee Research Award
  3. Australian National Health & Research Council Ideas Research Grant [1185813]

向作者/读者索取更多资源

Ciclesonide (CIC) is a promising prodrug for treating neonatal bronchopulmonary dysplasia (BPD) with limited adverse neurodevelopmental effects, activating glucocorticoid receptor (GR) in the lung without the systemic side effects associated with dexamethasone (DEX). Its potential in preventing fetal neurodevelopmental abnormalities caused by sGC use in pregnant women, such as in severe respiratory illnesses, makes CIC an attractive alternative to DEX.
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 antiinflammatory 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.

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