“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.”