ARCHIVED - New Hope for Strokes

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January 04, 2004— Ottawa, Ontario

A new international collaboration between NRC and researchers from Germany hopes to uncover new ways of preventing and managing the damage caused by strokes, a widespread and crippling affliction. A total of 50,000 Canadians suffer strokes each year (source, Canadian Stroke Network).

Benefits of Collaboration
German Flag
A Memorandum of Understanding between NRC and Germany's Helmholtz Association of Research Centres has resulted in 10 joint research projects. Dr. Danica Stanimirovic of the NRC Institute for Biological Sciences credits the agreement for helping propel a longstanding but informal relationship with the Institute for Molecular Pharmacology in Berlin into a significant international collaboration with major benefits.
For example, until now, when studying molecular change, scientists from both groups have been more-or-less obliged to work on a molecule-by-molecule basis. But, the project will allow both sides to combine expertise in proteomics and genomics to analyze change of a number of different targets at the same time.

"We will able to look at a spectrum of molecules at the same time. We can actually look at all the adhesion molecules, for example, and determine that out of more than 50 that we know exist, 10 have changed and identify the timelines where each has changed in the period after a stroke. This creates a more complete picture of the dynamic changes in the brain environment," Stanimirovic said.

Strokes are caused either by the rupture of blood vessels, which create significant damage, or the loss/reduction of blood circulation, which results in the loss of oxygen and nutrients to the brain, a condition known as ischemia. Strokes also cause disruptions in the blood-brain barrier, a network of tightly-sealed blood vessels in the brain. This shield is necessary to preserve the unique and highly specialized environment required for the brain to function properly. In the case of a stroke, the normally impenetrable blood-brain barrier is compromised, twice in fact, similar to an earthquake event and a subsequent aftershock. These disruptions cause openings in the barrier, which allow the entry of toxic blood components including proteins not normally found in the brain. These proteins are accompanied by water, resulting in the swelling of the brain and a condition known as brain edema .

Prevention and management of damage caused by strokes require a better understanding of brain blood vessels, a situation which researchers hope to address as part of this international collaboration project. According to project co-leader Dr. Danica Stanimirovic of the NRC Institute for Biological Sciences (NRC-IBS), the team will work to establish a clear molecular "fingerprint" of brain blood vessels both in normal state and in a disrupted state, such as what happens when the blood-brain barrier is breached. "This fingerprint would include specific information about what genes and proteins are expressed in a normal state and which ones are expressed in an altered state," she said.

Researchers already know that the two different blood-brain barrier openings generate different molecular activities within brain blood vessels. The first opening disrupts so-called "tight junctions", areas of extremely tight contacts between cells of the blood-brain barrier. "One focus of the research project will be to understand how tight junctions are disrupted by ischemia and what kinds of genes and proteins are changed, downregulated or degraded," Stanimirovic said. Team members from NRC-IBS partner, the Berlin-based Institute for Molecular Pharmacology, have extensive expertise in tight-junctions.

The second opening of the blood-brain barrier involves the activity of inflammatory cells, which are mobilized when the brain recognizes that a disruption has occurred. "Neurons and blood vessels talk. Different brain states mean that neurons and blood vessels are having different conversations and, as a result, the blood vessels are doing different things," Stanimirovic noted. Notably, the inflammation can be stopped, reducing further damage by stroke, if one can stop inflammatory cells from attaching themselves to the surface of brain endothelial cells. "There are many adhesion molecules that are expressed in response to ischemia in endothelial cells. One key variety that NRC-IBS has experience with is ICAM-1. One can disrupt this adhesion of inflammatory cells with specific antibodies against molecules such as ICAM-1," Stanimirovic stated.

A network of blood vessels (stained green) in brain tissue. Blood-brain barrier is the tightest in vessels with diameter less than 20 microns. One such vessel is shown in the upper corner at higher magnification. A network of blood vessels (stained green) in brain tissue. Blood-brain barrier is the tightest in vessels with diameter less than 20 microns. One such vessel is shown in the upper corner at higher magnification.

Ultimately, the brain blood vessels represent a unique and accessible target for helping treating stroke. The knowledge gained from the project will result in new ways of protecting and repairing the brain.

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