28th Spring Meeting Deutsche Gesellschaft für experimentelle
und klinische Pharmakologie und Toxikologie, Mainz, March 11-13, 1997
Class I metabotropic glutamate receptor agonists protect
rat hippocampal slices against hypoxic/hypoglycemic injury:
Timing and involvement of protein kinase C
U.H. Schröder, T. Jäger, T. Opitz, C.F. Sabelhaus, J. Breder,
and K. Reymann
During hypoxia and ischemia an excessive release of glutamate
eventually leads to sustained neuronal damage. To investigate
the influence of metabotropic glutamate receptors (mGluRs) on
neuronal injury caused by cerebral hypoxia/ischemia, we employed
an in vitro model of hypoxia/hypoglycemia.
Hippocampal slices from 7-week-old male Wistar rats were
transiently exposed to an oxygen and glucose free environment
in an interface chamber. The synaptically evoked population
spike in the CA1 region was taken as a measure of neuronal
viability.
Under control conditions the population spike amplitude
recovered incompletely (48.5±3.6 % of baseline values) within
one hour after termination of the hypoxic/hypoglycemic event.
The specific class I mGluR agonists trans azetidine2,4
dicarboxylic acid (trans ADA, 100 uM) and 3,5
dihydroxy-phenylglycine (DHPG, 10 uM) were highly protective
(89.3±3.8 % and 93.8 ±2.1% of baseline values respectively)
when applied before the event but not when applied later.
Co-application of the protein kinase C (PKC) inhibitors
staurosporine (100 nM) and chelerythrine (30 uM) reduced the
recovery rate to 39.3±7.9 % and 57.1±11.7% of baseline values
respectively.
It is concluded that the neuroprotection mediated by the
phospholipase C-coupled mGluRs involves PKC which must be
activated prior to or at the onset of hypoxia/hypoglycemia.
This study was supported by BMBF grant 0319998B.
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