A baby born in the U.S. today can look forward to statistical odds ofliving 75 years.

During that life span of 900 months, or 27,399 days, or 657,576hours or 39,454,560 minutes, his or her heart is pumping oxygen-laden blood to the brain non-stop. Should cardiac arrest shut downthat blood-flow for just four minutes _ one ten-millionth of that lifeexpectancy _ the brain begins to die.

That neuronal death sentence is pronounced by global ischemia _brain-wide oxygen starvation. But the identity of the executioner whoactually carries out the verdict has been under wraps.

It's less obscure now, thanks to a paper in today's Science titled:"The role of zinc in selective neuronal death after transient globalcerebral ischemia." The article's senior author is Dennis Choi,chairman of neurology at Washington University, in St. Louis.

"The sequellae of cardiac arrest are very severe," Choi toldBioWorld Today. "First of all, the majority of patients _ 1.5 millionannually in the U.S. _ die. An estimated 200,000 cases receiveattempted resuscitation," he continued, "of which maybe 70,000 aresuccessful. Only a minority of these, 15 percent or so, recover towhat's called a good outcome _ meaning they have enough of theirmental faculties back so they can get on with their lives." About halfof those who survive cardiac arrest leave the hospital with symptomsof brain damage.

The death of neurons over several days following a heart attackleaves most survivors with brain damage that affects memory andother mental and motor functions. Curiously, these ischemic deficitsselectively sap some regions of the brain, but leave others intact.Areas that suffer most are the hippocampus, seat of memory, theamygdala, a focus of emotion, and part of the cerebral cortex, whereconscious thought occurs.

From previous research, Choi suspected that the key perpetrator ofthis cerebral mayhem was a trace metal in the brain, namely zinc."That's the zinc that serves as a neurotransmitter," he said, "and webelieve serves as an injury agent following ischemia."

In the healthy brain, zinc acts at neuronal synapses, among otherpowerful effects, to down-regulate a receptor of the glutamateneurotransmitter.

"You should think of brain zinc," Choi explained, "as very differentfrom regular cell-biology zinc, which is pretty deeply embedded inthe woodwork. All those metalloproteins are not about to give uptheir atom of zinc. But the pool of `free' brain zinc," he continued,"is readily reactable."

Choi's Center for the Study of Nervous System Injury, at theUniversity, undertook to test the post-ischemia role of zinc in rats. Heand his co-authors prevented blood-borne oxygen from reaching therodents' brains for periods of time, after injecting a zinc-removingchelator, calcium EDTA, into their brain ventricles.

Using a fluorescent zinc-staining dye, he and his co-authors foundthat temporarily stopping blood flow to the rat brains led to a rapidincrease of zinc in nerve-cell bodies in the hippocampus, and in otherneurons. Their injected chelating agent prevented this zinc transfer,and reduced neuronal death.

"We found that that maneuver powerfully abated the phenomenon ofselective neuronal death, triggered by global ischemia," Choiobserved, and added, "That establishment of zinc's causality was thereal punch line of our paper in Science."

The experiments also showed "that the previously reportedassociation of zinc with nerve cell corpses was not a non-specificpost-mortem event. The zinc moves in at a point where we can showthat the neurons are still alive."

While pursuing further rat-based experiments to elucidate the zincmechanisms, Choi has "begun to wonder if the experimentalapproach that we used might not be adaptable to the clinic. We needto define the therapeutic window," he observed, "but it's not out ofthe question that administration of a zinc-chelating drug into thecerebrospinal fluid might be considered in human cardiacresuscitation."

As for human trials, he remarked: "One of the large questions in theindustry as a whole is to what extent, in thinking about brainischemia, to move directly from rodent model to man.

"One school of thought," he went on, "says, `Of course, it's importantto go to large primate models.' The other school says, `That's neitherhere nor there, because you're still going to be left with the question:Does it work in man?'"

Choi's own thought on the subject is: "Once you have a strongprobability case, what prevents you from going ahead with a trialwith humans, whom you have nothing else to offer anyway?"

He has a research alliance in this area with Hoffmann-La Roche, ofBasel, Switzerland, and the University has filed for patent protectionon the zinc-chelating approach.

The National Institute of Neurological Disorders and Stroke(NINDS), supports Choi's work. Thomas Jacobs, director of NINDS'stroke and trauma division, commented: "This report is the first toimplicate zinc as a contributor to neuron loss in ischemia. Theirfindings allow new ways of thinking about how the brain works,particularly under adverse conditions." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.