on February 26, 2009
Published online before print February 26, 2009, doi: 10.1161/STROKEAHA.108.535930
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Submitted on August 29, 2008
From the Institute of Physiology and Pathophysiology (C.R.W.K., D.C., V.L., H.J.L.), Johannes Gutenberg University of Mainz, Mainz, Germany; the Department of Experimental Neurophysiology (L.L., M.d.C.), Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta via Celoria 11, Milan, Italy; the Institute for Physiological Chemistry and Pathobiochemistry (T.P., C.U.P.), Johannes Gutenberg University of Mainz, Mainz, Germany; and the Institute for Physiology (V.L.), Otto-von-Guericke University, Magdeburg, Germany. * To whom correspondence should be addressed. E-mail: luhmann{at}uni-mainz.de.
Background and Purpose—Increased mortality after stroke is associated with brain edema formation and high plasma levels of the acute phase reactant C-reactive protein (CRP). The aim of this study was to examine whether CRP directly affects blood–brain barrier stability and to analyze the underlying signaling pathways. Methods—We used a cell coculture model of the blood–brain barrier and the guinea pig isolated whole brain preparation. Results—We could show that CRP at clinically relevant concentrations (10 to 20 µg/mL) causes a disruption of the blood–brain barrier in both approaches. The results of our study further demonstrate CRP-induced activation of surface Fc Conclusions—Our data identify a previously unrecognized mechanism linking CRP and brain edema formation and present a signaling pathway that offers new sites of therapeutic intervention.
Revised on October 8, 2008
Accepted on October 16, 2008
Mechanisms of C-Reactive Protein-Induced Blood–Brain Barrier Disruption
Christoph R.W. Kuhlmann MD;
receptors CD16/32 followed by p38-mitogen-activated protein kinase-dependent reactive oxygen species formation by the NAD(P)H-oxidase. The resulting oxidative stress increased myosin light chain kinase activity leading to an activation of the contractile machinery. Blocking myosin light chain phosphorylation prevented the CRP-induced blood–brain barrier breakdown and the disruption of tight junctions.
Key words: blood–brain barrier • edema • myosin light chain • stroke