Stroke: New approach to tackling the after-effects
An ischemic stroke leads to the destruction of the blood-brain barrier. The image shows capillaries in a brain section, above: healthy tissue, below: after a stroke. The tight-junction protein occludin is evidently greatly reduced in the image below taken after a stroke. (Photos: Dr. M. Burek)
To date, accumulations of fluid in the brain, which occur after a stroke, have been very difficult to treat. Researchers from the University of Würzburg have now found a solution to the problem. Their work is reported on in the journal Stroke.
Every year, more than 250,000 people in Germany suffer a stroke, and roughly one in three dies from the after-effects within the first year, making strokes the third most frequent cause of death in Germany. Stroke therapy often still poses major problems for doctors: after all, a blockage in a cerebral artery does not just cause the destruction of nerve cells suffering from decreased blood supply. One of the after-effects is also a leakage of fluid from the vessels into the brain, causing a cerebral edema.
This edema makes the tissue swell; the pressure on the surrounding area grows, eventually leading to the destruction of parts of the brain that are actually healthy as well. The reason for this is that the brain is trapped inside the bony shell of the skull and unable to expand.
Not all cerebral edemas are the same
It is no wonder that doctors try everything they can to stop a cerebral edema from even developing after a stroke – but with little success so far. “Cerebral edemas that occur with brain tumors or with a multiple sclerosis relapse, for example, can be treated relatively successfully with glucocorticoids, such as cortisone,” explains Professor Dr. Carola Förster from Würzburg University Hospital. Oddly enough, the same medications prove ineffective or even harmful when treating a stroke.
Carola Förster’s team has now managed to decipher the cause of this discrepancy in the effectiveness of steroids for different illnesses involving cerebral edemas. Stroke, the renowned journal of the American Heart Association, reports on this work in its latest issue.
Förster is a cell biologist and molecular endocrinologist. The professor runs the Department of Experimental Anesthesiology at the Clinic and Polyclinic for Anesthesiology. The blood-brain barrier, which normally ensures that the central nervous system is very well protected against outside influences, is one of her main research areas.
Oxygen deficiency is the trigger
“When a stroke occurs, oxygen deficiency in the affected area causes brain endothelial cells, in other words cells lining the vessels of the brain, to become more porous and therefore let fluids through more easily,” explains Förster. It is impossible to repair this porous barrier after a stroke with the help of glucocorticoids.
Förster has now discovered the reason why: what happens in the endothelial cells is that the oxygen deprivation causes the glucocorticoid receptors, which mediate the effect of these steroids, to deteriorate excessively. As a result, the cells lose the ability to respond to glucocorticoid therapy. “This effect seems to be confined to the vessels of the brain,” says Förster.
Förster and her team have also managed to identify the culprit for this deterioration. It is a proteasome, a biological system consisting of several enzymes. This observation opens up new avenues for scientists to find effective treatment: by inhibiting the proteasome early, they will be able to restore the glucocorticoid sensitivity of the endothelial cells. As a result, it will also be possible to reduce the cerebral edema after a stroke using medication such as cortisone.
Success in animal experiments as well
The new approach has already proven its effectiveness in animal experiments, as Würzburg neurologist Dr. Christoph Kleinschnitz has succeeded in demonstrating.
“What is special about our study is that not only could the results be observed in cell culture, they could also be transferred to mice who had suffered a stroke, making them significant in a living organism,” explains Kleinschnitz. This research could now provide a basis for making life-threatening brain swellings in stroke patients more treatable in the future.
Invention filed for
Carola Förster has already applied for a patent for her invention. However, she estimates that it could be another ten years before there is a drug on the market that can be used in people.
The study has been funded by the German Research Foundation within the scope of the Collaborative Research Center 688 as well as the European Union through the research association “Neurobid: Neuroscience on Barriers in Development”.
Glucocorticoid Insensitivity at the Hypoxic Blood–Brain Barrier Can Be Reversed by Inhibition of the Proteasome; Christoph Kleinschnitz, Kinga Blecharz, Timo Kahles, Tobias Schwarz, Peter Kraft, Kerstin Göbel, Sven G. Meuth, Malgorzata Burek, Thomas Thum, Guido Stoll, Carola Förster, PhD. Stroke. doi: 10.1161/STROKEAHA.110.592238
Contact:
Prof. Dr. Carola Förster, T: +49 (0)931 201-30012, e-mail: 
foerster_c@klinik.uni-wuerzburg.de
Dr. Christoph Kleinschnitz, T +49 (0)931 201-23755, e-mail: christoph.kleinschnitz@mail.uni-wuerzburg.de
30.03.2011, 08:45 Uhr