For release: Thursday, May 16, 1996
Much of the damage to neurons that results from blood loss to the brain during a heart attack stems from movement of zinc into oxygen-deprived neurons, a new study shows. This damage can largely be prevented by injecting a substance that mops up the zinc between cells. The findings may lead to new strategies for preventing brain damage caused by heart attack and some kinds of surgery.
The new study shows for the first time that zinc is a major player, rather than a bystander, in neuronal death that follows ischemia (is-KEE-me-a), or loss of blood flow and oxygen to the brain. This neuron death, which occurs over a period of several days, is responsible for many of the problems with memory and other functions that often follow a heart attack. The new findings suggest that measures which reduce zinc movement into neurons can protect against brain damage from ischemia, says Dennis W. Choi, M.D., Ph.D., of Washington University in St. Louis, Mo., who led the new study. The results, funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), appear in the May 17 issue of Science.
This report is the first to implicate zinc as a contributor in neuron loss due to ischemia. "We thought, all along, that it was [the neurotransmitter] glutamate that causes nerve cell death through calcium overload," says Thomas P. Jacobs, Ph.D., of the Division of Stroke and Trauma at NINDS. Dr. Choi and his colleagues "have now looked at something entirely different," Dr. Jacobs says. "Their findings allow new ways of thinking about how the brain works, particularly under adverse conditions."
Previous studies from Dr. Choi's laboratory have shown that excessive amounts of zinc, which normally serves as a signaling chemical, can cause neurons to die in culture. Other laboratories have shown that, after loss of oxygen, zinc moves from the signal-releasing fibers of one set of neurons into the cell bodies of other neurons which have been damaged. Whether zinc's movement into the damaged neurons occurs before or after the neurons begin dying, however, has been unclear until now.
Using a fluorescent zinc-staining dye, Dr. Choi and his colleagues found that temporarily stopping blood flow in the brains of rats led to a rapid decrease of zinc in nerve-signaling fibers in the hippocampus, followed by the appearance of zinc in other neurons. While zinc levels in the signaling fibers gradually returned to normal, the neurons that took up the zinc degenerated and eventually died. Zinc uptake preceded degenerative changes in these neurons. Injecting a chemical which efficiently binds to zinc like a magnet 30 minutes before ischemia blocked the zinc influx into hippocampal neurons and the ensuing neuronal degeneration. This chemical, calcium EDTA, cannot penetrate cell membranes and thus stays in the space between cells, where it can tie up zinc before it reaches vulnerable neurons.
Zinc's role in ischemia-related neuron death may help explain why some brain regions are commonly damaged by lack of blood flow while others go unscathed. The commonly damaged regions include the hippocampus, which is important for memory; the amygdala, which is linked to emotion; and part of the cortex, where conscious thought occurs. Neuron loss in these and other ischemia-sensitive regions is thought responsible for the problems often experienced by people who have had heart attacks or major surgical procedures, such as heart valve replacements and heart bypass surgery. These problems may include memory loss and motor problems. "The cells that die don't contain zinc until after ischemia," says Dr. Jacobs. "If you can block the flow of zinc into these neurons, you may prevent them from dying."
While zinc appears necessary for neuron death after ischemia, agents that cause excitotoxicity -- neuron death from overstimulation -- can kill neurons in the absence of zinc. However, zinc's role in cell death does not necessarily conflict with studies that implicate excitotoxicity in ischemia, Dr. Choi says. He believes the processes of zinc damage and excitotoxicity may be intertwined. For example, zinc may enter the cell through the calcium channels in cell membranes that are opened by glutamate, which plays a key role in excitotoxicity and also is released during ischemia. The presence of zinc in neurons which do not normally contain it might then act together with calcium overload to disrupt a variety of cellular functions.
Zinc is an extremely important trace element in the human body. In addition to its signaling functions, it is thought to play a role in enzymatic processes such as those of superoxide dismutase (SOD), which is important for detoxifying "free radicals," or super-reactive molecules that can wreak havoc with many parts of a cell's machinery. The new evidence shows that zinc, like many other chemicals in the body, is good in small amounts but disastrous in excess, says Dr. Jacobs. "In many cases, the substances that kill neurons and other cells are the ones we need in lesser amounts," he adds.
The new findings open a promising new area of research that ultimately may lead to ways of preventing some of the brain dysfunction associated with heart attacks and major heart surgery, which affect millions of Americans each year. Scientists now must define how zinc leads to neuron death and find ways to interfere with this process, Dr. Choi says.
The NINDS, one of the National Institutes of Health in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally designated Decade of the Brain.
Koh, J.-Y.; Suh, S.W.; Gwag, B.J.; He, Y.Y.; Hsu, C.Y.; Choi, D.W. "The Role of Zinc in Selective Neuronal Death After Transient Global Cerebral Ischemia." Science, Vol. 272, No. 5264, May 17, 1996.
Originally prepared by Latalie Larsen, NINDS Office of Communications and Public Liaison.
Last Modified August 7, 2009