The metal zinc is an essential dietary nutrient, present
as a component of many proteins in all the cells of our
bodies. Zinc aids the function of many enzymes, and helps
regulate the use of genes as templates for making new
proteins. It also has a special function as a signaling
substance - a neurotransmitter - in the central nervous
system. It is stored within nerve endings, and released
to the space outside nerve cells during nervous system
activity, together with other neurotransmitter substances,
in particular glutamate. The normal functional effects
of zinc are mediated in large part by its ability to alter
the behavior of certain glutamate receptors, receptor
proteins on the surface of the membrane of the nerve cells
that recognize glutamate and consequently cause the nerve
cell to become electrically active.
Despite this important normal function of zinc, recent
studies have suggested that zinc may also be a key mediator
of the nerve cell death associated with several types
of disease conditions, including temporary loss of blood
flow as occurs during a cardiac arrest (heart stoppage)
followed by resuscitation. If loss of blood flow lasts
longer than several minutes, brain damage can result,
even if all other organs return to normal function. This
brain damage typically causes memory disturbances and
other difficulties, or even coma if severe enough.
Certain brain neurons are known to be especially susceptible
to death induced by transient loss of blood flow. My colleagues
and I have modeled this process of neuronal death by transiently
reducing brain blood flow in rats for 10 minutes. Although
brain blood flow was completely restored after this 10
minute deprivation period, certain selectivity vulnerable
brain nerve cells went on to die over the next 1-3 days,
just as after cardiac arrest in humans. These selectivity
vulnerable rat nerve cells contained notably large quantities
of zinc. To test the idea that excessive zinc entry into
the cells caused their death, we injected a blockage substance,
calcium-EDTA, into the ventricles (fluid-filled spaces)
of the rat brains. The calcium-EDTA trapped the zinc released
from nerve endings before it could enter the cells; as
a result many fewer nerve cells filled with zinc and went
on to die.
Our results suggest that brain zinc stores, while presumably
useful for normal brain function, might also have a dangerous
side, becoming killers of nerve cells after a transient
lowering in blood flow. We are presently performing studies
to determine exactly how excessive amounts of zinc entry
may kill nerve cells. We hope that strategies designed
to interfere with zinc entry into nerve cells, or the
specific consequences of that entry for nerve cell metabolism,
may lead to the development of novel treatments which
might be used in the future to reduce brain damage in
patients suffering form cardiac arrest.
