Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum.
Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum.
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DOI：
10.1016/j.nbd.2021.105422
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发表时间：
2021-08
影响因子：
6.1
通讯作者：
DeFranco DB
中科院分区：
文献类型：
--
作者：
Jaumotte JD;Franks AL;Bargerstock EM;Kisanga EP;Menden HL;Ghersi A;Omar M;Wang L;Rudine A;Short KL;Silswal N;Cole TJ;Sampath V;Monaghan-Nichols AP;DeFranco DB
合成糖皮质激素(SGC)，如地塞米松(DEX)，虽然用于缓解患有严重支气管肺发育不良(BPD)的早产儿的炎症和疾病进展，但也与显著的不良神经效应有关，如髓鞘形成减少和神经解剖发育异常。环索奈德(CIC)是一种sgc前体药物，被批准用于治疗哮喘，其全身副作用有限。富含在下呼吸道的羧酸酯酶将CIC转化为糖皮质激素受体(GR)激动剂DES-CIC。因此，我们研究了CIC是否同样会激活新生儿肺中的GR，但对肺外的不良影响有限，特别是在发育中的大脑。新生大鼠于出生后第1~5天(PND1~PND5)皮下注射CIC、DEX或赋形剂。在接受CIC治疗的新生儿中，没有观察到与地塞米松暴露有关的全身影响，包括体重和大脑重量减轻。此外，CIC不会引发新生儿DEX暴露引起的大脑皮层髓鞘碱性蛋白表达的长期减少，也不会导致小脑大小的长期减少。反之，DEX和CIC均能有效诱导新生大鼠肺组织GR靶基因的表达，包括参与肺保护和抗炎作用的基因。因此，CIC可激活新生儿肺内GR，对神经发育的不良影响有限，是治疗或预防新生儿BPD的一种有前途的新型候选药物。此外，由于早产孕妇服用地塞米松等sGC会对胎儿大脑发育产生不利影响，因此CIC的神经保护特性使其成为治疗患有严重呼吸道疾病(如哮喘加重或新冠肺炎感染)的孕妇的有吸引力的替代方案。
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.
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影响因子：
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