Excessive Ca2+ influx through
NMDA receptor-coupled channels has been linked to neuronal cell death. Using an in vitro model of transient
brain ischemia, we investigated possible protective effects of
NMDA receptor antagonists
ketamine or
MK-801 and of
calmidazolium, an inhibitor of intracellular Ca2(+)-activated
proteins.
Brain ischemia/recovery was simulated in isolated hippocampal slices and injury monitored by measurement of
ATP levels. Omission of both
glucose and
oxygen (but not
oxygen alone) for 20 min led to persistent
ATP deficits after 4 h recovery. Addition of
ketamine or
MK-801 at 1 microM permitted
ATP to recover within 1 h, as did addition of
calmidazolium at 10 microM. Our findings are consistent with other reports that
NMDA receptor antagonists can protect neuronal tissue from ischemic damage. The role of inappropriately activated Ca2(+)-mediated signaling processes in the mechanism(s) of such injury is suggested by the protection also seen with
calmidazolium, an inhibitor of
calmodulin and other structurally related
proteins such as
calpain(s) and
protein kinase C. The inhibition of intracellular Ca2+ target
proteins may be an alternative for protection of the brain against injury due to insults that activate
NMDA receptors.