Universität zu Köln

Luh, Clara, Feiler, Sergej, Frauenknecht, Katrin ORCID: 0000-0002-1372-3297, Meyer, Simon, Lubomirov, Lubomir T., Neulen, Axel ORCID: 0000-0003-3547-1630 and Thal, Serge C. (2019). The Contractile Apparatus Is Essential for the Integrity of the Blood-Brain Barrier After Experimental Subarachnoid Hemorrhage. Transl. Stroke Res., 10 (5). S. 534 - 546. NEW YORK: SPRINGER. ISSN 1868-601X

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Abstract

Development of vasogenic brain edema is a key event contributing to mortality after subarachnoid hemorrhage (SAH). The precise underlying mechanisms at the neurovascular level that lead to disruption of the blood-brain barrier (BBB) are still unknown. Activation of myosin light chain kinases (MLCK) may result in change of endothelial cell shape and opening of the intercellular gap with subsequent vascular leakage. Male C57Bl6 mice were subjected to endovascular perforation. Brain water content was determined by wet-dry ratio and BBB integrity by Evans-Blue extravasation. The specific MLCK inhibitor ML-7 was administered to the mice to determine the role of the contractile apparatus of the neurovascular unit in determining brain water content, BBB integrity, neurofunctional outcome, brain damage, and survival at 7 days after SAH. Inhibition of MLCK significantly reduced BBB permeability (Evans Blue extravasation - 28%) and significantly decreased edema formation in comparison with controls (- 2%). MLCK-treated mice showed reduced intracranial pressure (- 53%), improved neurological outcome at 24 h and 48 h after SAH, and reduced 7-day mortality. Tight junction proteins claudin-5 and zonula occludens-1 levels were not influenced by ML-7 at 24 h after insult. The effect of ML-7 on pMLC was confirmed in brain endothelial cell culture (bEnd.3 cells) subjected to 4-h oxygen-glucose deprivation. The present study indicates that MLCK contributes to blood-brain barrier dysfunction after SAH by a mechanism that does not involve modulation of tight junction protein levels, but via activation of the contractile apparatus of the endothelial cell skeleton. This underlying mechanism may be a promising target for the treatment of SAH.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Luh, Clara UNSPECIFIED UNSPECIFIED UNSPECIFIED Feiler, Sergej UNSPECIFIED UNSPECIFIED UNSPECIFIED Frauenknecht, Katrin UNSPECIFIED orcid.org/0000-0002-1372-3297 UNSPECIFIED Meyer, Simon UNSPECIFIED UNSPECIFIED UNSPECIFIED Lubomirov, Lubomir T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Neulen, Axel UNSPECIFIED orcid.org/0000-0003-3547-1630 UNSPECIFIED Thal, Serge C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-133374
DOI:	10.1007/s12975-018-0677-0
Journal or Publication Title:	Transl. Stroke Res.
Volume:	10
Number:	5
Page Range:	S. 534 - 546
Date:	2019
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1868-601X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MYOSIN LIGHT-CHAIN; CEREBRAL EDEMA; RHO-KINASE; INHIBITION; PRESSURE; PHOSPHORYLATION; DYSFUNCTION; DISRUPTION; EXPRESSION; CALCIUM Multiple languages Clinical Neurology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13337