Curbing stroke’s inflammatory damage: A new target

by Nancy Fliesler on March 28, 2012

Brain MRIs from mice after stroke. Mice lacking Hv1 (right panels) had a much smaller volume of infarcted tissue than normal mice. Hv1 can also be blocked chemically.

Whether it’s in adults or in children with clotting disorders or other conditions such as sickle-cell disease, a stroke can be likened to an atomic bomb. Just as ongoing radiation can do more damage than the bomb itself, the secondary damage of a stroke can devastate the brain.

In an ischemic stroke, accounting for nearly 90 percent of all stroke cases, it happens like this: When vessels supplying blood and oxygen to the brain are blocked by a narrowing or a clot, immune cells in the brain sense the low-oxygen conditions, suspect an invading organism and try to kill it by producing molecules known as reactive oxygen species or ROS’s. These, unfortunately, have an inflammatory effect that actually damages the brain further, injuring and killing neurons.

“Stroke produces inflammation, and that’s one of the main things people have been after in trying to reduce stroke damage,” says David Clapham, MD, PhD, chief of the Basic Cardiovascular Research Laboratories at Boston Children’s Hospital.

Right now there’s nothing that can do this. Most existing stroke drugs are aimed at preventing the stroke or dissolving blood clots once the stroke is happening – but they can’t deal with the aftermath.

Some clinical trials have tried to buffer the inflammatory effects of ROS molecules in diseases such as atherosclerosis, using traditional antioxidants like vitamin E, but results have been disappointing.

Other researchers have proposed using drugs to suppress the enzyme that helps churn out the toxic ROS molecules. Mice genetically engineered to lack this enzyme, known as NOX, show less brain injury after stroke. But since NOX is actually a whole family of enzymes, found in many kinds of cells in the body, inhibiting it would have too many side effects.

Eliminating or blocking this channel would head off production of toxic ROS molecules after stroke.

Clapham and colleagues had an idea. They’d been working with a molecule called Hv1, a gate-like protein known as an ion channel that sits on the cell surface and regulates the buildup of electrical charges in the cell. Hv1 enables NOX to function by, in essence, keeping the cell electrically balanced.

Could taking Hv1 out of the picture—thus blocking ROS production—minimize stroke damage?

Clapham’s team compared two groups of mice—normal “wild-type” mice and genetically engineered mice that were unable to make Hv1. The Hv1 “knockout” mice indeed had less ROS production in their brain cells. And, as reported earlier this month in Nature Neuroscience, and shown in the image above, they also had a lower infarct volume—less death of tissue—on magnetic resonance imaging at both 24 and 72 hours after the stroke.

“What’s exciting about this approach is that it’s showing a more effective way of mitigating secondary damage from stroke,” says Ed Smith, MD, co-director of the Neurosurgical Stroke Program at Boston Children’s. “It would not stop the atomic bomb from going off, but it could have a huge effect in minimizing the fallout.”

The beauty of disabling Hv1 is that it can be done chemically, Clapham says. Moreover, it’s found mainly in inflammatory cells, so blocking it would have a more specific and beneficial effect. Hv1 inhibitors do exist, so Children’s hopes to partner with industry to do preclinical studies.

Interestingly, one of the cell types in the brain that carries Hv1 is microglia. These cells are like double agents: Like immune cells, they churn out ROS’s in response to low-oxygen conditions. But they also function as brain cells, helping to shape synaptic connections between neurons. So, potentially, inhibiting Hv1 in these cells would protect the very cells that could help the brain recover function after a stroke.

“This research offers a targeted approach specific to the areas where it’s needed,” says Smith.  “Another advantage is rapidity: Ion channel management usually has a fairly immediate effect. The fact that there are existing compounds that theoretically could be tried in people is very exciting.”

There may even be benefits beyond stroke. “Targeting Hv1 may be useful for any inflammatory process,” says Clapham. That might include arthritis, cellular aging and even Alzheimer’s disease—which also involves inflammation in the brain and which Clapham’s team is in the early stages of investigating in mice.

[Editor's Note: For more information or to learn about partnership opportunities related to this technology, please contact Children's Technology and Innovation Development Office by email or phone at (617) 919-3019.]

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