Brain Saver: Compound might shield neurons during stroke (Stroke)
Authors: Leslie Mitch 
Published: August 2003

A fragment of a brain protein might limit the damage from stroke by preventing cells from committing suicide. Although it's still in animal trials, the compound could give doctors a few extra hours in which to treat a stroke.

The mainstay of stroke treatment today is tissue plasminogen activator (tPA), which can restore blood flow through a blocked vessel by dissolving the clot. But time restricts tPA's benefits. To ward off brain damage, patients usually must receive the drug within 3 hours of the stroke. Yet doctors can't give tPA until they are sure the stroke stems from a clot rather than from a leaking blood vessel, a condition the drug would exacerbate. Moreover, tPA restarts blood flow, but it doesn't protect cells against inflammation and other forms of injury that arise from stroke.

One compound that might provide that protection is NAP, an eight-amino-acid snippet of a larger brain protein. NAP had previously shown promise in guarding cells against oxidative damage and in saving mice with head injuries. To gauge its protective prowess, Ronen Leker, a neurologist at Hadassah University in Jerusalem, and colleagues induced strokes in rats by blocking an artery that feeds part of the brain. Some of the rats received a NAP injection, whereas others got saline. The researchers then judged the severity of brain damage with standard tests of disability, such as whether the rats could move out of a circle within a set amount of time or whether they veered toward the stroke-damaged side when walking. The team also measured the size of the brain lesions.

Compared to controls, the NAP-treated animals scored better on the disability tests, and their brain lesions were about 50% smaller. These differences were still evident after 30 days. The benefits appeared only if the rats got NAP within 4 hours of the stroke. Although the findings are preliminary, they suggest that NAP could extend the treatment window for stroke, says Leker. Four hours in rats translates into roughly 6 or 7 hours for people, which means extra time for patients to get to the hospital for diagnosis.

Further tests indicated that NAP might work by hindering apoptosis, or cellular suicide. Cells from the control rats were more likely to contain DNA fragments, a hallmark of apoptosis, and the enzyme caspase, which drives this cell death process. "What's unique is that NAP works at very low concentrations," says neuroscientist Illana Gozes of Tel Aviv University in Israel, who was also on the team.

A small, potent molecule that easily enters and permeates the brain is just what doctors are clamoring for, says Kyra Becker, a stroke neurologist at the University of Washington, Seattle. However, she cautions that the literature is full of promising compounds that flopped in human trials. One interpretation of the results, she adds, is that positive effects of NAP might extend beyond preventing cell suicide: "The bottom line is that I'm not sure it matters how it works, as long as it does work."

--Mitch Leslie; suggested by Lynnette Gerhold

R. R. Leker, A. Teichner, N. Grigoriadis, H. Ovaida, D. Brenemann, M. Fridkin, E. Galudi, J. Romano, I. Gozes, NAP, a femtomolar-acting peptide, protects the brain against ischemic injury by reducing apoptotic death.
Stroke
33
, 1085-1092 (2002).
[Abstract]
[Full Text]