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

Neurobiology of Disease

Anthony Rudine¹  Alexis L. Franks¹  Neerupama Silswal¹  Alexis Ghersi¹  Venkatesh Sampath¹  Donald B. DeFranco²  A. Paula Monaghan-Nichols³  Erin M. Bargerstock⁴  Mahmoud Omar⁵  Edwina Philip Kisanga⁶  Timothy J. Cole⁷  Kelly L. Short⁷  Juliann D. Jaumotte⁷  Heather L. Menden⁷  Liping Wang⁷ 

[1] Pittsburgh Institute of Neurodegenerative Disease (PIND), University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;;Department of Biochemistry &Department of Neonatology, St. David's Medical Center, Austin, TX, USA;Department of Pediatrics, Division of Child Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;Department of Pediatrics, Division of Neonatology, Children's Mercy Kansas City, University of Missouri Kansas City School of Medicine, Kansas City, MO, USA;Department of Pediatrics, Division of Newborn Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA;

关键词: Ciclesonide;    Dexamethasone;    Bronchopulmonary dysplasia;    Glucocorticoids;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown