By Dean A. Haycock

Special To BioWorld Today

Earlier this month, when the news media reported on a paper in the February 1998 issue of Nature Medicine about the potentially neurotoxic effects of a well-known stroke treatment, some subtleties were lost in the translation between science and journalism. The news concerned a report that tPA, a proven treatment for stroke, could contribute to neuronal damage in mice.

"Some of the press still ran with the dangers of tPA even though I told them [about the positive aspects of this study]. I think that is a disservice because the overall effect is beneficial," the senior author of the paper, Stuart Lipton, chief of the Cerebrovascular and Neuroscience Research Institute at Brigham and Women's Hospital, in Boston, told BioWorld Today. "I really emphasized to them this was good news because it gave us a new pathway to consider to make the effect of tPA even better."

While acknowledging tPA's beneficial effects in stroke victims, the authors of the report, "Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice," suggested the "therapeutic intervention with tPA in the nervous system may represent a two-edged sword."

An important feature of the paper, according to Lipton, is the increased understanding it provides of tPA's activities, which should help researchers develop even better stroke treatments.

"I really think we should put a positive spin on this. TPA is still the best drug we have for stroke and it works. It works in humans. Ours is a mouse study, after all," Lipton said.

An opinion piece written by Gregory del Zoppo of the Scripps Research Institute in the same issue of Nature Medicine questioned the applicability of the research in mice to the use of the drug in the clinic, where it has earned a good track record. A spokesman for South San Francisco-based Genentech Inc. agreed.

"It is very difficult to include studies in mice and correlate them into human stroke victim studies. I think that tPA for stroke has been very well analyzed and, in fact, there are new follow-up data presented at the recent American Heart Association that showed the drug is very safe when it is used appropriately. Physicians who use tPA should be very well educated on its risks and benefits," said Paul Laland, Genentech's director of corporate communications.

Located in brain tissue and small blood vessels, tPA converts plasminogen to plasmin, which dissolves blood clots. It is the first agent to be approved by the FDA to destroy clots and restore blood flow in the brains of stroke victims. Marketed by Genentech as Activase, recombinant tPA is meant to be administered within three hours of the onset of acute ischemic stroke. Clinical studies have demonstrated that when used as indicated in the correct patient population, it can improve disabilities in a significant number of stroke victims.

Neuronal damage following a stroke is thought to be caused in large part by the release of excitatory agents such as glutamate, which "overstimulate" neurons, leading to their destruction.

Lipton and his colleagues had been studying mice that lack natural tPA. They found that these animals are resistant to the nerve-killing effects of an excitotoxin such as glutamate when it is directly injected into the brain. This lack of susceptibility to a treatment that kills brain cells in normal mice implies that naturally occurring tPA found in neurons and glia may directly contribute to the damage caused by excitotoxins released during a stroke.

Because tPA, a serine protease enzyme, could become a widespread treatment for stroke, the researchers decided to see if it contributed to the death of neurons that follows cerebral ischemia, interrupted blood flow to the brain.

Using a method that blocks the middle cerebral artery without causing a blood clot, the researchers induced strokes in tPA-deficient mice and in controls. This experimental procedure, involving the insertion and later withdrawal of a nylon filament coated with silicone into the artery, allowed the scientists to analyze the effects of tPA's presence or absence, independent of the enzyme's clot-busting activities.

Other Drugs May Offset TPA-Induced Damage

The results were striking. TPA-deficient mice suffered an approximate 50 percent reduction in the size of cerebral infarcts, areas of brain cell damage, compared with wild-type, control mice.

Furthermore, injecting tPA into the two strains of mice produced larger areas of damage than seen in control animals. This led the authors to suggest that "since tPA promotes desirable [thrombolytic] as well as undesirable [neurotoxic] outcomes during stroke, future therapies should be aimed at countering the excitotoxic damage of tPA to afford even better neuroprotection after an acute cerebral infarct."

They suggested tPA might be improved as a stroke treatment by decreasing its neurotoxic effects while retaining its clot-dissolving properties.

"In fact, we now have drugs in the lab we are actively looking at — some of which are in the pharmacopoeia for other indications. This will be quite surprising when we release the names," Lipton said.

Other compounds under study are new and the subject of patent applications.

"I think we will be able to use this knowledge to actually improve treatment — for example, to give tPA in combination with something else to offset these neurotoxic effects and still reap the benefits of its clot-busting," Lipton told BioWorld Today.

In the meantime, it is too early to say how the new data will affect Genentech's studies of tPA.

"As with any research, we incorporate such findings into a very large database," Laland said. Activase was first approved in 1987 for treatment of heart attacks. *

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