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Multiple Antenatal Dexamethasone Treatment Alters Brain Vessel Differentiation in Newborn Mouse Pups
Winfried Neuhaus1, Marian Schlundt2, Markus Fehrholz3
1Department of Anaesthesia and Critical Care, University of Wuerzburg, Wuerzburg, Germany; Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria; Institute of Medical Genetics, Medical University of Vienna, Vienna, Austria.
Insights
Antenatal dexamethasone treatment in mice negatively impacts brain vessel development and blood-brain barrier (BBB) integrity. Multiple doses significantly downregulated key molecular markers crucial for brain vascularization and function.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Antenatal steroid treatment matures fetal lungs but may adversely affect brain development.
- Glucocorticoids like dexamethasone are used for fetal lung maturation.
- Repeated exposure to antenatal steroids has been linked to long-term neurodevelopmental issues.
Purpose of the Study:
- To investigate the effects of antenatal dexamethasone on brain vessel differentiation and blood-brain barrier (BBB) phenotype in a mouse model.
- To analyze key molecular markers associated with brain vascularization and BBB function.
Main Methods:
- Established a mouse model for antenatal dexamethasone exposure.
- Analyzed molecular markers in total brain samples and isolated brain endothelial cells at postnatal days 4 and 10.
- Utilized techniques including staining for Pecam-1/CD31 and claudin-5, and mRNA level analysis.
Main Results:
- Triple antenatal dexamethasone treatment significantly downregulated claudin-5, Pecam-1/CD31, glucocorticoid receptor, NR1 subunit, and ABC transporters in postnatal day 4 brains.
- Effects were less pronounced with single treatment or at postnatal day 10.
- Downregulation of angiogenesis markers (sonic hedgehog, Wnt pathway) observed, suggesting altered brain vascularization.
Conclusions:
- Multiple antenatal dexamethasone treatments adversely affect brain vessel differentiation and BBB integrity at a molecular level.
- The findings provide a basis for understanding the neurodevelopmental risks associated with repeated antenatal glucocorticoid exposure.
- Further research is needed to explore long-term consequences and potential mitigation strategies.
Abstract:
Antenatal steroid treatment decreases morbidity and mortality in premature infants through the maturation of lung tissue, which enables sufficient breathing performance. However, clinical and animal studies have shown that repeated doses of glucocorticoids such as dexamethasone and betamethasone lead to long-term adverse effects on brain development. Therefore, we established a mouse model for antenatal dexamethasone treatment to investigate the effects of dexamethasone on brain vessel differentiation towards the blood-brain barrier (BBB) phenotype, focusing on molecular marker analysis. The major findings were that in total brains on postnatal day (PN) 4 triple antenatal dexamethasone treatment significantly downregulated the tight junction protein claudin-5, the endothelial marker Pecam-1/CD31, the glucocorticoid receptor, the NR1 subunit of the N-methyl-D-aspartate receptor, and Abc transporters (Abcb1a, Abcg2 Abcc4). Less pronounced effects were found after single antenatal dexamethasone treatment and in PN10 samples. Comparisons of total brain samples with isolated brain endothelial cells together with the stainings for Pecam-1/CD31 and claudin-5 led to the assumption that the morphology of brain vessels is affected by antenatal dexamethasone treatment at PN4. On the mRNA level markers for angiogenesis, the sonic hedgehog and the Wnt pathway were downregulated in PN4 samples, suggesting fundamental changes in brain vascularization and/or differentiation. In conclusion, we provided a first comprehensive molecular basis for the adverse effects of multiple antenatal dexamethasone treatment on brain vessel differentiation.
