Inhibiting ion channels to curb stroke’s inflammatory damage
David Clapham of Boston Children’s and colleagues are developing a new strategy to stop the secondary damage of stroke.
A stroke can be likened to an atomic bomb. Just as radiation poisoning can do more damage than the bomb itself, the secondary damage of a stroke, caused by release of reactive oxygen species (ROS) produced by the brain’s immune cells, can devastate the brain. Right now, no therapy can stop that secondary damage.
David Clapham, MD, PhD, chief of the Basic Cardiovascular Research Laboratories at Boston Children’s Hospital, and colleagues are developing a new strategy to stop the secondary damage. They have found that removing Hv1, an ion channel that regulates the buildup of electrical charges in the cell, doesn’t allow ROS production in the first place, thereby minimizing stroke damage.
Dr. 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, they also had a lower infarct volume—less death of tissue—on magnetic resonance imaging at both 24 and 72 hours after a stroke.
“What’s exciting about this approach is that it’s showing a more effective way of mitigating secondary damage from stroke,” says Edward 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, Dr. Clapham says. Moreover, it’s found mainly in inflammatory cells, so blocking it would have a more specific and beneficial effect.
Research grade Hv1 inhibitors do exist, and can be used to continue to explore the biology of Hv1 and associated pathways. In order to have clinical impact, however, molecules suitable for pharmaceutical development are needed. Children’s hopes to partner with industry to use Hv1 as a target for chemical compound screening.
This approach could be better than the current standard of care, which is aimed at the prevention of blood clots that cause stroke but doesn’t deal with the aftermath. Strategies to treat the aftermath like the use natural antioxidants, such as Vitamin E, have been disappointing and drugs that suppress the enzyme which helps release the toxic ROS molecules have a plethora of side effects.
“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.
Cover image courtesy of Brookhaven National Laboratory.
[Editor's Note: For more information or to learn about partnership opportunities related to this technology, please contact Boston Children's Technology and Innovation Development Office or phone (617) 919-3019.]