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The Journal of Neuroscience, January 15, 2003, 23(2):384-391
 PKC Is Required for the Induction of Tolerance by Ischemic and
NMDA-Mediated Preconditioning in the Organotypic Hippocampal Slice
Ami P.
Raval1,
Kunjan
R.
Dave1,
Daria
Mochly-Rosen2,
Thomas J.
Sick1, and
Miguel A.
Pérez-Pinzón1
1 Cerebral Vascular Disease Research Center, Department
of Neurology and Neuroscience, University of Miami School of Medicine,
Miami, Florida 33101, and 2 Division of Chemical Biology,
Department of Molecular Pharmacology, Stanford University School of
Medicine, Stanford, California 94305
Glutamate receptors and calcium have been implicated as triggering
factors in the induction of tolerance by ischemic preconditioning (IPC)
in the brain. However, little is known about the signal transduction
pathway that ensues after the IPC induction pathway. The main goals of
the present study were to determine whether NMDA induces
preconditioning via a calcium pathway and promotes translocation of the
protein kinase C  (PKC) isozyme and whether this PKC isozyme is
key in the IPC signal transduction pathway. We corroborate here that
IPC and a sublethal dose of NMDA were neuroprotective, whereas blockade
of NMDA receptors during IPC diminished IPC-induced neuroprotection.
Calcium chelation blocked the protection afforded by both NMDA and
ischemic preconditioning significantly, suggesting a significant role
of calcium. Pharmacological preconditioning with the nonselective PKC
isozyme activator phorbol myristate acetate could not emulate
IPC, but blockade of PKC activation with chelerythrine during IPC
blocked its neuroprotection. These results suggested that there might
be a dual involvement of PKC isozymes during IPC. This was corroborated
when neuroprotection was blocked when we inhibited PKC during IPC
and NMDA preconditioning, and IPC neuroprotection was emulated with the
activator of PKC. The possible correlation between NMDA,
Ca2+, and PKC was found when we emulated IPC with
the diacylglycerol analog oleoylacetyl glycerol, suggesting an indirect
pathway by which Ca2+ could activate the
calcium-insensitive PKC isozyme. These results demonstrated that the
PKC isozyme played a key role in both IPC- and NMDA-induced tolerance.
Key words:
metabolism; in vitro cultures; glutamate receptors; anoxia; tolerance; signal transduction
Copyright © 2003 Society for Neuroscience 0270-6474/03/232384-08$05.00/0
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