Scientists Find New Trigger For Nerve Cell Death

October 03, 1997

St. Louis, Oct. 3, 1997 -- A paper in today's Science challenges a well-established idea about why nerve cells self-destruct when the brain or spinal cord is injured or becomes diseased. It suggests that when potassium jumps ship, neurons commit suicide.

"If our hypothesis proves correct, it will open up new possibilities for protecting nerve cells in patients who suffer stroke, head injury, spinal cord injury or neurodegenerative disorders such as Alzheimer's disease," says Dennis W. Choi, M.D., Ph.D., the Jones Professor and head of neurology at Washington University School of Medicine in St. Louis.

Choi, who directs the Center for the Study of Nervous System Injury, was the senior investigator in the study. The novel idea was the brainchild of lead author Shan Ping Yu, M.D., Ph.D., research assistant professor of neurology.

In the hours or days after the brain is injured, healthy cells surrounding the damaged region also die, killing themselves through a genetically controlled process called programmed cell death or apoptosis. Scientists previously have focused attention on changes in the amount of calcium contained within cells undergoing apoptosis. But Yu's experiments suggest that a mass exodus of potassium may be just as important as changes in calcium.

Potassium ions cross the cell membrane through tunnels called potassium channels, which control the rate at which they flow. If these channels play a key role in apoptosis, it might be possible to use drugs called potassium channel blockers to stem potassium loss and prevent nerve cells from dying. This might restrict damage to the initially injured area of the brain or spinal cord, allowing patients to recover more fully.

Yu got his idea by considering how apoptotic cells differ from those in the throes of necrosis -- sudden death at the focus of an injury. Whereas necrotic cells swell up and burst, apoptotic cells shrink into oblivion. "A shrinking cell must be losing ions and water," Yu says.

Potassium seemed like the obvious ion to escape because there's so much of it in the cell. Yu therefore measured potassium movement through the membranes around cultured nerve cells after various events that cause apoptosis.

Six hours after the neurons were deprived of serum, the current flowing out through one type of potassium channel had increased by 61 percent. By 9 hours, the amount of potassium inside the cells had dropped by 13 percent. The potassium currents in cells that were dying by necrosis didn't change, however.

To determine whether potassium loss triggers apoptosis or is simply a side effect, Yu blocked potassium channels with a compound called TEA (tetraethylammonium). The potassium channel blocker reduced the number of cells that died after serum withdrawal, suggesting that potassium loss is indeed a trigger for apoptosis.

Reducing potassium loss by increasing the amount of potassium in the solution bathing the cells also prevented apoptosis. This protective effect was seen even in the presence of a substance that prevents calcium from flowing into cells.

"These experiments don't rule out a role for calcium in apoptosis," Yu says. "But they do suggest that potassium outflow is independently an important mechanism."

Moreover, the potassium changes preceded apoptosis. "So potassium loss appears to play a critical early role, telling neurons to commit suicide," Yu says.

The group now is looking to see whether TEA or other potassium channel blockers can reduce brain damage in rats that have suffered a stroke.

Meanwhile, Yu and colleagues have found that TEA or elevated levels of extracellular potassium protect cultured neurons from beta-amyloid peptide, a substance that may kill brain cells in Alzheimer's disease. Again, these effects occur even in the presence of a calcium channel blocker. "These data suggest that manipulating potassium channels also may provide a new therapeutic strategy for slowing neuronal degeneration in Alzheimer's disease," Choi says.

Yu SP, Yeh C-H, Sensi SL, Gwag BJ, Canzoniero LMT, Farhangrazi ZS, Ying HS, Tian M, Dugan LL, Choi DW. Mediation of neuronal apoptosis by enhancement of outward potassium current. Science vol. 278, 3 Oct., 1997.

A grant from the National Institutes of Health supported this work.

Washington University School of Medicine

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