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C1 Esterase Inhibitor Reduces BBB Leakage and Apoptosis in the Hypoxic Developing Mouse Brain

  • Susan Jung
  • Hans-Georg Topf
  • Gudrun Boie
  • Regina TrollmannEmail author
Original Paper

Abstract

Inflammatory pathways involved in blood–brain barrier (BBB) vulnerability and hypoxic brain oedema in models of perinatal brain injury seem to provide putative therapeutic targets. To investigate impacts of C1-esterase inhibitor (C1-INH; 7.5–30 IU/kg, i.p.) on functional BBB properties in the hypoxic developing mouse brain (P7; 8% O2 for 6 h), expression of pro-apoptotic genes (BNIP3, DUSP1), inflammatory markers (IL-1ß, TNF-alpha, IL-6, MMP), and tight junction proteins (ZO-1, occludin, claudin-1, -5), and S100b protein concentrations were analysed after a regeneration period of 24 h. Apoptotic cell death was quantified by CC3 immunohistochemistry and TUNEL staining. In addition to increased apoptosis in the parietal cortex, hippocampus, and subventricular zone, hypoxia significantly enhanced the brain-to-plasma albumin ratio, the cerebral S100b protein levels, BNIP3 and DUSP1 mRNA concentrations as well as mRNA expression of pro-inflammatory cytokines (IL-1ß, TNF-alpha). In response to C1-INH, albumin ratio and S100b concentrations were similar to those of controls. However, the mRNA expression of BNIP3 and DUSP1 and pro-inflammatory cytokines as well as the degree of apoptosis were significantly decreased compared to non-treated controls. In addition, occludin mRNA levels were elevated in response to C1-INH (p < 0.01). Here, we demonstrate for the first time that C1-INH significantly decreased hypoxia-induced BBB leakage and apoptosis in the developing mouse brain, indicating its significance as a promising target for neuroprotective therapy.

Keywords

Neonatal brain injury S100b protein Hypoxia Neuroprotection Tight junctions Occludin Matrix metalloproteinases BNIP3 DUSP1 

Abbreviations

BBB

Blood–brain barrier

BNIP3

BCL2 Interacting Protein 3

C1-INH

C1 esterase inhibitor

CC3

Cleaved caspase 3

DUSP1

Dual specificity phosphatase 1

FOV

Field of view

HI

Hypoxia and ischemia

HIF

Hypoxia-inducible transcription factors

MMP

Matrix metalloproteinase

TIMP

Tissue inhibitor of metalloproteinases

ZO-1

Zona occludens protein 1

IL

Interleukin

TNF-alpha

Tumour necrosis factor-alpha

Notes

Funding

This work was supported by an unrestricted research grant from CSL Behring (RT, HGT)

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12017_2019_8560_MOESM1_ESM.pdf (318 kb)
Electronic supplementary material 1 (PDF 318 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Susan Jung
    • 1
  • Hans-Georg Topf
    • 2
  • Gudrun Boie
    • 1
  • Regina Trollmann
    • 1
    Email author
  1. 1.Division of Neuropediatrics, Department of PediatricsFriedrich-Alexander University Erlangen-NürnbergErlangenGermany
  2. 2.Division of Neonatology, Department of PediatricsFriedrich-Alexander University Erlangen-NürnbergErlangenGermany

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