Drug Target for Stimulating Recovery from Stroke Discovered

 Investigators at the Stanford University School of Medicine have shown that removing a matched set of molecules that typically help to regulate the brain's capacity for forming and eliminating connections between nerve cells could substantially aid recovery from stroke even days after the event. In experiments with mice, the scientists demonstrated that when these molecules are not present, the mice's ability to recover from induced strokes improved significantly.

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Importantly, these beneficial effects grew over the course of a full week post-stroke, suggesting that, in the future, treatments such as drugs designed to reproduce the effects in humans might work even if given as much as several days after a stroke occurs. The only currently available stroke treatment -- tissue plasminogen activator, or tPA -- must be given within a few hours of a stroke to be effective, and patients' brains must first be scanned to determine whether this treatment is appropriate. Moreover, while tPA limits the initial damage caused by a stroke, it doesn't help the brain restore or replace lost connections between nerve cells, which is essential to recovery.

The mice in the study had been genetically bioengineered to lack certain molecules that one of the Stanford researchers had previously shown to play a major role in modulating the ease with which key nerve-cell connections are made, strengthened, weakened or destroyed in the brain. The molecules in question include "K" and "D," two of the 50 or so members of the so-called MHC class-1 complex, which plays a key role in the function of the immune system. Alternatively, when a receptor called PirB, which binds to these MHC molecules, is not present, the same improved outcome from stroke happens -- significant, because receptors make good drug targets.
It was only a few years ago that Carla Shatz, PhD, professor of neurobiology and of biology, and her colleagues surprised the neuroscience and immunology communities by showing that these molecules "moonlight" in the brain, where their job appears to involve inhibiting the readiness of connections among nerve cells (known as synapses) to grow stronger or weaker in response to experience.
Learning and memory require the constant, coordinated strengthening of some synaptic connections and weakening of others. But this very flexibility, if it becomes excessive, is thought to put the brain at risk for conditions such as epilepsy or schizophrenia. The molecules Shatz has been exploring can be seen as providing a measure of stabilizing ballast.
However, in order to re-establish brain functions that have been lost in the massive nerve-cell die-off that follows an extraordinary event such a stroke, it's necessary to restore lost synapses and form new ones at a rapid pace. It's also important to retrain surviving circuits to take over functions formerly served by lost circuits -- this is the basis of rehabilitation therapy. Under such circumstances, one might ask, might it be a good idea to ease up on the brake pedal?
"Nobody had ever thought any of these molecules had anything to do with stroke," said Shatz, who is the Sapp Family Provostial Professor and also is the director of Bio-X, Stanford's interdisciplinary biosciences research consortium. "But our lab had shown in 2009 that mice bioengineered to lack them performed like Olympians on motor-learning tasks."
A couple of years ago, Shatz and her colleague, Rona Giffard, MD, PhD, professor of anesthesia and a veteran stroke researcher, grew bored during a scientific meeting and began whispering about their work "to cheer ourselves up," Shatz said. It occurred to them that teaming Shatz's molecules with Giffard's animal-research expertise could provide answers to this question.
The results, published Mar. 22 in Neuron, were unequivocal and potentially quite clinically significant: Mice genetically engineered to lack either K and D or PirB, a major cell-surface receptor for these molecules, experienced markedly better recovery in their motor performance after a stroke than did normal mice. Giffard and Shatz are the senior authors of the Neuron study.
"This is the very first time anyone has looked for a role of these molecules in stroke, or in recovery from stroke," said Giffard. "Targeting recovery, as opposed to just halting the damage, would have the widest possible chance to help patients after stroke, and could help patients who cannot receive tPA."
The collaboration was accelerated by the fact that Jamie Adelson, a PhD candidate in Shatz's laboratory who shared first authorship of the study with postdoctoral researcher George Barreto, PhD, of Giffard's lab, had worked in the Giffard lab before joining Shatz's group.
Tests indicated that concentrations of K and D -- which in a healthy brain are already abundant at synapses -- rose dramatically in the brain after an induced stroke.
First the researchers trained their mice in certain athletic activities, such as balancing on a spinning horizontal rod at gradually increasing rotation speeds, or traversing the rungs of a small "ladder" suspended horizontally just a half-inch or so above a board. Then the researchers induced strokes in the trained animals by cutting off blood supply to a region of the brain that is involved in motor performance. One week later, the animals lacking K and D had recovered their athletic skills substantially better than the normal animals had. Moreover, lab tests showed that the stroke-affected area of the K/D-deficient mice was considerably smaller than was the case for the controls.

**Published in "SCIENCE DAILY"