Novel inhibitor offsets neurotoxic effects of tPA -

A research team lead by the Burnham Institute has synthesized and tested a new series of inhibitors that can prevent the type of nerve cell injury and death associated with many neurodegenerative diseases and stroke. The study, led by Stuart Lipton, MD, PhD, professor and director of Burnham's Del E. Webb Center for Neuroscience and Aging Research, is published in the July issue of the Journal of Neuroscience.

There is but one medical treatment approved for stroke, the third leading cause of death in the United States: tissue plasminogen activator ("tPA"). tPA must be administered within 3 hours of stroke onset to restore the flow of blood to the brain. Unfortunately, treatment with tPA can also contribute to nerve cell damage. In recent years, medical scientists have begun to understand that tPA activates an entire family of enzymes, called matrix metalloproteinases, that normally regulate how cell structures are held together.

Dr. Lipton, together with first author Dr. Zezong Gu, and other colleagues at Burnham, University of Notre Dame, and Wayne State University in Detroit, have found that a molecule called SB-3CT blocks the activity of one member of the metalloproteinase family, called MMP-9.

Previous work at Burnham and elsewhere has shown that damage to the brain triggers excessive activity among MMPs, especially MMP-9. The enzymes degrade cell structures, inducing cell death and escalating brain damage in mice. In the current study, the researchers determined the particular mechanism of action for MMP-9. In doing so, they identified a new drug target and, armed with this knowledge, generated a lead therapeutic compound, SB-3CT.

"MMPs have been targeted for stroke therapy, but other drugs have had side effects," said Lipton. "This was due to the fact that therapies hit all MMPs, and not just the ones causing the nerve cell damage. Additionally, previous drugs had side effects on other organs in the body. Here, SB-3CT acts only on MMP-9 and other closely related MMPs, so we may be able to create a new generation of drugs without the side effects we've been seeing."

Dr. Shahriar Mobashery of the University of Notre Dame developed SB-3CT and related new drugs, believed to be "smarter" antagonists to block MMPs. Using the new drug, the research team led by Lipton and Gu found that SB-3CT protected against brain damage in mice undergoing a stroke, compared to mice that did not receive the molecular treatment. In SB-3CT treated mice, MMP-9 activity dropped significantly, while other MMPs showed no activity changes. SB-3CT reduced brain damage to only 30% of that seen in control mice receiving a placebo drug. In addition, SB-3CT appeared to preserve neurological function and behavior in mice undergoing a stroke. Finally, significant therapeutic action of SB-3CT was seen up to six hours after the initial damage. While a mouse study may not be immediately applicable to humans, the results indicate the potential of this kind of molecular blocker.

Lipton's team, who had first described the mechanism of activation of MMPs in the brains after stroke and other damage, found that MMP-9 in particular is activated by either trauma or a rise in levels of nitric oxide, a gaseous substance implicated in stroke and degenerative diseases. Once activated, MMP-9 begins to break down structures in the nerve cell, leading to damage and disease.

Lipton and his team believe that SB-3CT or similar drugs, if proven effective in further studies, may be able to be used alone as a treatment, or in combination with tPA. "tPA activates MMPs, which can result in nerve damage," said Lipton. "In combination, however, SB-3CT could preserve the action of tPA as a clot buster, while preventing concurrent nerve damage," he suggests. "This would improve stroke therapy."

The researchers are now working on chemical derivatives of SB-3CT, to determine the chemical formula that best blocks the activity of MMP-9 in the safest possible manner.

Other coauthors contributing to this work include Drs. Stephen Brown, University of Notre Dame; Rafael Fridman, Wayne State University, Detroit, Michigan; and Jiankun Cui and Alex Strongin of The Burnham Institute.

The study was supported by grants from the National Institutes of Health.

The Burnham Institute, founded in 1976, is an independent not-for-profit biomedical research institution dedicated to advancing the frontiers of scientific knowledge and providing the foundation for tomorrow's medical therapies. The Institute is home to three major centers: its original Cancer Center, the Del E. Webb Neuroscience and Aging Center established in 1999, and the Infectious and Inflammatory Disease Center dedicated in 2004. Since 1981, the Institute's Cancer Center has earned the prestigious designation as a Non-comprehensive Cancer Center by the National Cancer Institute. Discoveries by Burnham scientists have contributed to the development of new drugs for Alzheimer's disease, heart disease and several forms of cancer. Today the Burnham Institute employs over 700, including more than 550 scientists. The majority of the Institute's funding derives from federal sources, but private philanthropic support is essential to continuing bold and innovative research. For additional information about the Institute and ways to support the research efforts of the Institute, visit www.burnham.

Gu, Z, Cui, J, Brown, S, Fridman, R, Mobashery, S, Strongin, AY, and Lipton, SA, "A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia", J. Neuroscience, released July 6, 2005

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