Activase, also known as tissue plasminogen activator, or tPA, has been on the market for almost 10 years as a treatment for ischemic stroke.

But apparently, while tPA giveth to stroke victims with one hand, the other hand taketh away. The drug is an effective clotbuster, but one of its side effects is that it activates matrix metalloproteinases (MMPs), enzymes that chew up the extracellular matrix. Since stroke itself also activates MMPs, tPA is effectively exacerbating one of the harmful consequences of stroke at the same time as it is breaking up the clot that leads to stroke in the first place.

"The net effect of tPA is positive," stressed Stuart Lipton, director of the Del E. Webb Center for Neurosciences and Aging at the Burnham Institute. "But how much better would it be if we could prevent the ill effects?"

In the July 6, 2005, issue of the Journal of Neuroscience, researchers from the Burnham Institute, the University of Notre Dame in Indiana and Wayne State University in Detroit suggested that specific MMP inhibitors, which already are being developed to fight cancer metastases, could be successful in neuroscience for such prevention of ill effects. Their data show that inhibiting matrix metalloproteinases might be a way to combat some of tPA's side effects.

Inhibiting MMPs to prevent cancer metastases has long been a goal of drug development, and after a string of clinical failures with nonspecific inhibitors, new compounds are showing preclinical promise for another go at the strategy. Part of this comeback is based on the development of so-called "suicide inhibitors" that have a novel mechanism of action and improved specificity compared to first-generation, broad-spectrum MMP inhibitors; in May, scientists (including Rafael Fridman at Wayne State University and Shahriar Mobashery of the University of Notre Dame, who also are co-authors on the paper) reported that one such inhibitor, SB-3CT, reduced liver metastases and lengthened survival time in an aggressive mouse model of T-cell lymphoma. (See BioWorld Today, May 11, 2005.)

MMPs are activated in the brain after a stroke, Lipton said, and attack that extracellular matrix, a connective tissue that is one way that neurons stay connected to one another.

"And if they disconnect, they die," he told BioWorld Today.

The researchers did not directly test whether SB-3CT can inhibit matrix metalloproteinases activated by tPA; instead, they investigated whether SB-3CT can prevent the MMP activation in a mouse model of stroke itself, which also activates matrix metalloproteinases. However, given that MMP activation is a well-known effect of tPA administration, Lipton is confident that the compound will work on MMP activated by tPA, as well as by stroke.

"Stroke itself activates MMPs, and tPA merely adds to the damage," he said, adding that "we're pretty conservative in our models, and in our hands, this model has had good predictive capacity."

SB-3CT protected against brain damage in mice undergoing a stroke; the compound reduced brain damage to only 30 percent of that seen in control mice receiving placebo. In addition, SB-3CT appeared to preserve neurological function and behavior in mice undergoing a stroke.

In SB-3CT treated mice, MMP-9 activity dropped significantly, while other MMPs showed no activity changes.

Significant therapeutic action of SB-3CT was seen when the drug was administered up to six hours after stroke induction; while it is not directly possible to extrapolate to the effective time window in humans, one of the problems bedeviling tPA, which has not achieved the market penetration one might expect for a drug that is the only FDA-approved medication for the treatment of ischemic stroke, is that it needs to be administered within three hours of stroke - a time point at which many stroke victims have not made it to the emergency room yet, let alone out of triage and into treatment.

Lipton noted that the scientists are working on developing improved versions of SB-3CT. He and his team believe that SB-3CT or similar drugs, if proved effective in further studies, might be able to be used alone or in combination with tPA to treat stroke.

He also said that in the area of neurology, SB-3CT will prove useful for neurodegenerative diseases, as well as stroke treatment. The researchers are in discussions with several companies to further the clinical development of SB-3CT for neurological indications. Lipton is optimistic about the prospects of specific MMP inhibitors to pan out in the clinic, and says that overall, the paper gives "further hope for a line of research that was considered dead not that long ago."

No Comments