Sci. Aging Knowl. Environ., 22 September 2004
Blocking pH-sensitive calcium channels prevents stroke damage
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/38/nf87
Acid burns brains that suffer strokes, and a new study suggests why. The work identifies a channel protein that unleashes a dangerous calcium torrent when pH drops. Drugs that cinch up the channel might help save the brains of stroke patients.
When a stroke chokes off the brain's blood supply, neurons suffocate and die. Doctors have few weapons in their arsenal to minimize the destruction, and they're tracking down exactly why brain cells perish in order to devise new treatments. After a stroke, calcium floods into cells, killing them by unleashing enzymes that chew up proteins and DNA. Researchers have suspected that receptor proteins that bind the neurotransmitter glutamate enable the calcium deluge. Glutamate amounts rise during a stroke, and receptor proteins that glom onto glutamate allow calcium into cells. But compounds that hamper glutamate receptors have failed in human trials for stroke despite promising results in animals, leading scientists to seek other treatment avenues. Previously, researchers had identified proteins that shuttle calcium ions across the cell membrane when pH drops. Strokes acidify the brain, so neurophysiologist Zhi-Gang Xiong of the Legacy Clinical Research and Technology Center in Portland, Oregon, and colleagues investigated whether these acid-sensitive proteins--known as ASICs--contribute to the calcium glut and cell death.
First, the researchers treated cultured mouse neurons with acid and measured calcium entry into the cells. As they lowered the pH, more calcium flowed. Adding a chemical that blocks ASICs quenched the flow. In addition, cells that received the ASICs-plugging molecule were more likely to survive acid treatment than were untreated cells. A molecule that stymies glutamate receptors did not prevent acid-inflicted harm. Next, the team mimicked the effects of a stroke by lowering pH and depriving cell cultures of oxygen and glucose; cellular calcium amounts soared. Blocking ASICs kept calcium concentrations low and saved neurons.
To investigate whether ASICs worsen strokes in animals, the team tied off brain arteries in rats for 100 minutes. One day later, animals that had received ASICs-clogging drugs displayed approximately 60% less brain damage than did untreated animals. Moreover, genetically altered mice that don't produce ASICs preserved more brain cells after a stroke than did normal animals. Together, the results suggest that a stroke-induced pH drop spurs ASICs to allow calcium into neurons and that crippling these proteins protects brains against stroke damage. Giving rodents ASICs blockers and glutamate-receptor drugs together reduced the extent of stroke damage better than administration of the glutamate blockers alone, says Xiong. Researchers suspect that successful treatment of strokes will require multiple drugs, so further studies should test whether this tandem also works in humans, he says.
"It's a big deal," says stroke researcher Raymond Swanson of the University of California, San Francisco. "We've known for 20 or 30 years" that elevated acid amounts can exacerbate stroke damage, and this study suggests why, he says. Strokes kill other brain cells besides neurons, notes neurologist Richard Kraig of the University of Chicago. Future studies should investigate how acid catastrophes in neurons render other cells more vulnerable, he says. Perhaps controlling acid will help buffer human brains from stroke.
September 22, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150