From the Center for the Study of Neurological Disease, The Queen's
Medical Center, Honolulu, Hawaii.
Correspondence to Tibor Kristián, PhD, Center for the Study of Neurological Disease, The Queen's Medical Center, University Tower 8th Floor, 1356 Lusitana St, Honolulu, HI 96813. E-mail tibor{at}www.cns.queens.org
Background—This review article deals
with the role of calcium in ischemic cell death. A
calcium-related mechanism was proposed more than two decades ago to
explain cell necrosis incurred in cardiac ischemia and muscular
dystrophy. In fact, an excitotoxic hypothesis was advanced to explain
the acetylcholine-related death of muscle end plates. A similar
hypothesis was proposed to explain selective neuronal damage in the
brain in ischemia, hypoglycemic coma, and status
epilepticus.
Summary of Review—The original concepts encompass the hypothesis
that cell damage in ischemia-reperfusion is due to enhanced
activity of phospholipases and proteases, leading to release of free
fatty acids and their breakdown products and to degradation of
cytoskeletal proteins. It is equally clear that a coupling exists
between influx of calcium into cells and their production of
reactive oxygen species, such as ·O2-,
H2O2, and ·OH. Recent results have
underscored the role of calcium in ischemic cell death. A
coupling has been demonstrated among glutamate release, calcium influx,
and enhanced production of reactive metabolites such as
·O2-, ·OH, and nitric oxide. It
has become equally clear that the combination of
·O2- and nitric oxide can yield
peroxynitrate, a metabolite with potentially devastating effects. The
mitochondria have again come into the focus of interest. This is
because certain conditions, notably mitochondrial calcium accumulation
and oxidative stress, can trigger the assembly (opening) of a
high-conductance pore in the inner mitochondrial membrane. The
mitochondrial permeability transition (MPT) pore leads to a collapse of
the electrochemical potential for H+, thereby arresting ATP
production and triggering production of reactive oxygen
species. The occurrence of an MPT in vivo is suggested by the dramatic
anti-ischemic effect of cyclosporin A, a virtually specific
blocker of the MPT in vitro in transient forebrain ischemia.
However, cyclosporin A has limited effect on the cell damage incurred
as a result of 2 hours of focal cerebral ischemia, suggesting
that factors other than MPT play a role. It is discussed whether this
could reflect the operation of phospholipase A2 activity
and degradation of the lipid skeleton of the inner mitochondrial
membrane.
Conclusions—Calcium is one of the triggers involved in
ischemic cell death, whatever the mechanism.
© 1998 American Heart Association, Inc.
Basic Science Review
Calcium in Ischemic Cell Death
Key Words: calcium • cerebral ischemia • free radicals • mitochondria
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