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Calling all pharmacologists: Stroke-recovery mechanism found, small molecule needed

There are at least three big problems with the early medical treatment from stroke: First, the only approved drug, tissue plasminogen activator or tPA, has to be infused within a few hours of the stroke. Second, the patient must first be scanned to rule out a type of stroke for which tPA would be precisely the wrong thing to infuse. And third, while tPA does break up the clotting that is responsible for most strokes, it doesn't actually do anything to stimulate recovery in affected brain regions - or even to prevent the stroke from continuing to spread beyond the initial lesion for a time due to inflammatory processes that ensue.

But with the infusion of some venture capital and a bit of patience, a whole new approach - one that may actually help the brain recover and replace its damaged circuitry - could see the light of day.

In a collaboration (reported today in the journal Neuron) between the labs of neuroscience experts Carla Shatz, PhD, and Rona Giffard, MD, PhD, mice missing the gene for one or another of a particular set of molecules were able to recover their athletic ability much better than mice carrying those genes, which are ordinarily present in their genomes - and ours.

Interestingly, the molecules in question are associated with crucial tasks performed by the immune system. But that's just their day-job. It was only a few years ago that Shatz demonstrated that these molecules are moonlighting in brain, where they do something entirely different: They serve as "brakes" on the formation, enhancement, diminution, and destruction of connections between nerve cells. In other words, they limit the brain's propensity to alter these connections in response to experiences.

Ordinarily, one might think that the more amenable the brain is to experience-driven modulation, the better. But as noted in my release concerning the new study:

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 stablizing ballast.

However, after a stroke, when re-establishing lost or damaged brain functions is paramount and time is of the essence, what could be more important than restoring lost nerve connections or quickly forming new ones? Might easing up on the brake pedal under those circumstances possibly be a good idea?

The Shatz/Giffard study suggests the answer might be yes. But demonstrating this in a way that will lead to stroke recovery in our species, or at least to clinical trials in humans - will require an agent a bit more subtle than deleting a gene. A small molecule that could get into the brain quickly and impede the molecular brakes - the MHC molecules and their receptor - from engaging for a finite period of time instead of permanently would be just what the doctor ordered.

But that will have to await the beneficent intervention of a pharmaceutical company, a biotech, or an academic molecule manipulator. "We're not pharmacologists," says Shatz.

Any takers?

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