Feb. 6, 2001 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 patients.
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 inhibitor."
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 revascularization.
The study was funded by the National Institutes of Health and by a grant from Merck KgaA.
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