A Target for Stroke Therapy Drugs
Every year, nearly 800,000 people in the U.S. suffer a stroke. It’s the country’s third-leading cause of death, and a primary cause of severe, long-term disability—the damage it does to the brain is largely irreparable. But a study published online yesterday in the journal Nature describes how a drug helped repair the brains of mice to a degree that was previously impossible. This breakthrough happened because of the discovery of a neural signaling system in the brain that plays a role in recovering from a stroke.
A stroke is usually caused by a clot that blocks blood flow to an area of the brain. Tissue in that part of the brain dies from lack of oxygen unless the clot is detected immediately and is either dissolved or removed. The dead tissue cannot be revived, but often the brain can be trained to redirect nerve impulses via still-living nearby neurons. But such training is difficult, can require months to years of arduous rehab, and is often not sufficient to overcome complex disability.
The new research, by neurologist S. Thomas Carmichael and his colleagues at the University of California at Los Angeles, shows that neurons in the areas of the brain closest to the site of a stroke are impaired after it occurs. The reason for that is a buildup of an inhibitory signaling molecule called GABA that prevents the neurons from firing. When those nerves are inhibited, it’s harder for the brain to recruit them into its rerouted circuits.
In studies in mice, the researchers discovered that blocking a particular piece of the GABA signaling system with an existing drug allowed the nerves to reactivate, reversing the repressed excitability, allowing them to more easily respond to other neurons, and encouraging and enhancing early recovery after a stroke by as much as 50 percent. “At face value, it’s a new pharmacological target for repair and recovery in stroke,” Carmichael says.
That’s no small feat. Currently, the only drug that’s known to help with post-stroke recovery is tissue plasminogen activator, or tPA, which breaks up clots and can be very effective at restoring blood flow to the brain when administered within the first few hours after a stroke. But tPA can only be used in a small subset of patients (because it dissolves all blood clots, which can lead to harmful side effects), and can’t help restore lost brain function—it only helps prevent tissue from dying in the first place. Despite decades of research, there are no known drugs that can encourage brain repair after a stroke, and the only proven techniques for recovering lost function involve frequent and intense physical therapy.
“We’ve been kind of stalled in stroke recovery, and I think this is a very interesting approach. It’s very encouraging, and it’s a new direction,” says Dale Corbett, a stroke researcher at the University of Ottawa. “This is really the first thing that’s come along that’s a nonphysical therapy approach that’s quite exciting.”
Carmichael and his colleagues identified the piece of the GABA signaling cascade that goes awry in the area of the brain adjacent to the stroke: reduced levels of a transporter responsible for moving the inhibitory molecule out of the vicinity. Without that transporter, GABA is allowed to reach such high levels that the nearby neurons are prevented from firing.
In studies in mice, the researchers induced a stroke in the motor cortex, the movement center of the brain, and then gave them a drug that specifically reverses the post-stroke GABA uptake. The drug is not approved for use in people—it was an experimental molecule produced during the drug industry’s search for memory enhancers. But just the fact that it works in mice means that stroke researchers have a new line of evidence to pursue.
“It’s significant, because they’re identifying a molecular mechanism that is keeping stroke survivors from recovering. And as a result, [Carmichael is] identifying targets for molecular manipulation,” says Theresa Jones, a neurobiologist at the University of Texas at Austin. “Now we have potential to find drugs that aim at that target.”
The scientists found that, as with other types of stroke treatments, timing was critical. During the first few days after a stroke, a brain injury is still stabilizing; prior studies have shown that any physical rehabilitation attempted during this period can aggravate the brain and actually make the damage worse. The same proved true for the drug.
But when the mice were given the drug three days later, it improved their recovery of movement by 40 to 50 percent. This implies that while the post-stroke inhibition of neurons in these areas may help with immediate recovery, but it is a harmful adaptation when it persists for weeks or months or even years after the initial injury.
Researchers still need to do a huge amount of work before they can determine whether this approach will work in humans. “The stroke field has famously screwed this part up for about 25 years—you have to make sure you’re really understanding what you’re doing before you go to human studies,” Carmichael says. He plans to do similar studies with other kinds of stroke, in other areas of the brain. At the same time, he says, “my hope is that we can start to interface with the pharmaceutical industry. They’ve been pursuing this class of drugs, and it would be worthwhile to push this toward a clinical trial.”
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