X-Message-Number: 15565
From: Brent Thomas <>
Subject: interesting preventative for brain distress resulting from stroke
Date: Tue, 6 Feb 2001 09:27:00 -0500 

from http://www.sciencedaily.com/releases/2001/02/010205074740.htm

could perhaps be used as an additional protectant before

Scientists Suggest Novel Therapy To Limit Tissue Damage Following Stroke 

La Jolla, CA, January 31, 2001 -- Scientists at The Scripps Research
Institute (TSRI), along with their colleagues at Henry Ford Health Sciences
Center, Detroit, report findings in the current issue of Nature Medicine
suggesting a novel therapeutic target that appears to prevent tissue damage
caused by stroke. 
According to lead author David A. Cheresh, Ph.D., Professor, Departments of
Immunology and Vascular Biology at TSRI, "Our findings suggest a possible
new modality to complement the effects of thrombolytic therapy, the only
therapeutic option currently available for stroke patients." 

The research article, "Src deficiency or blockage of Src activity in mice
provides cerebral protection following stroke," is authored by Robert Paul,
Zheng G. Zhang, Brian P. Eliceiri, Quan Jiang, Antonio D. Boccia, Rui L.
Zhang, Michael Chopp, and David A. Cheresh. 

Stroke is one of the most common causes of adult disability in the United
States. According to the National Institute of Neurological Disorders and
Stroke, more than 500,000 Americans suffer a stroke each year, resulting in
approximately 160,000 deaths annually. Currently, the only treatments for
the condition are clot-dissolving drugs, including tissue plasminogen
activator (TPA) and streptokinase. 

A stroke is associated with decreased blood flow to the brain caused by a
thrombus or rupture of a blood vessel. This leads to reduced oxygen in the
brain, setting off a cascade of events triggering brain damage. The
resulting low level of oxygen in the brain triggers the local blood vessels
to become leaky. It is this leakiness that results in edema (fluid
accumulation) in the brain leading to intracranial pressure which often
causes extensive brain damage. This process represents one of the major
complications associated with stroke. 

The scientists reasoned, then, that identifying a mechanism to regulate
vascular permeability, or leakiness, following the onset of stroke may have
a significant influence on the progression and severity of the disease.
Therefore, the discovery that a specific enzyme inhibitor could block this
cascade and thereby disrupt vascular leakiness following stroke represents a
new approach to the possibility of limiting injury in the brain of stroke

This process is initiated by a molecule called VEGF/VP, which is naturally
produced in the brain of stroke patients, in response to decreased oxygen in
tissues. While it is designed to promote the growth of new blood vessels --
a process known as angiogenesis -- it also produces the vascular
permeability that causes irreparable harm in stroke patients. In a previous
study, Cheresh and colleagues discovered that a particular enzyme, referred
to as Src kinase, played a key role in the VEGF/VP permeability effect on
blood vessels. The researchers hypothesized that if they could inhibit the
Src kinases' activities, they could interrupt the cascade of effects leading
to stroke's debilitating consequences. 

In this study, the researchers found that mice lacking the Src gene product
were unable to undergo vascular permeability and demonstrated reduced
neuronal damage following a stroke incident. Further, by administering a Src
kinase inhibitor up to 6 hours following stroke, the scientists were able to
limit longer-term brain damage in mice following stroke. The Src inhibitor
proved to suppress VEGF-induced vascular permeability, resulting in
decreased edema, improved cerebral perfusion and oxygenation, and reduced
infarct size following stroke. 

According to Cheresh, "This data speaks to the potential clinical impact of
Src blockade in the treatment of human stroke. Further, Src inhibition
increased the neurological score at 24 hours and the survival rate over the
course of 7 days following stroke after a single injection of the compound.
Repeated applications may further improve the long-term effect of the

Src inhibitors are thought to disrupt the growth of certain cancers by
reducing their oncogenic potential. This study demonstrates a new use for
the compound, in preventing tissue damage due to increased VEFG-mediated
vascular permeability. Further, the scientists believe that administration
of the compound within several hours following stroke may reduce brain
injury and possibly prevent long-term neurological damage without disrupting

The study was funded by the National Institutes of Health and by a grant
from Merck KgaA. 

Editor's Note

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