Protective effect of group I metabotropic glutamate receptor activation against hypoxic/hypoglycemic injury in rat hippocampal slices: timing and involvement of protein kinase C

Excessive release of glutamate during ischemia leads to sustained neuronal damage. In this study we investigated the influence of metabotropic glutama te receptor (mGluR) activation on neuronal recovery from a hypoxic/hypoglyc emic event in hippocampal slices from rats. The slices were transiently exp osed to an oxygen- and glucose-free environment in an interface chamber and the synaptically evoked population spike in the CA1 region was taken as a measure of neuronal viability. Under control conditions the population spik e amplitude recovered to 41.4% of baseline value within 1 h after hypoxia/h ypoglycemia. The specific mGluR group I agonist 3,5-dihydroxyphenylglycine (DHPG, 10 mu M) increased the recovery rate to 88.3% of baseline value when applied from 20 min before until 10 min after the event. Similar recovery rates were obtained when DHPG was present only 10 or 20 min before hypoxia/ hypoglycemia (89.3% and 79.3% of baseline value, respectively). However, wh en applied later, DHPG had no protective effect. Go-application of the prot ein kinase C (PKC) inhibitors staurosporine (100 nM) or chelerythrine (30 m u M) prevented the protective effect of DHPG. Our data suggest that group I mGluR agonists are only protective when present prior to the onset of the hypoxic/hypoglycemic event and that the activation of PKC is a critical ste p of the protective mechanism. (C) 1999 Elsevier Science Ltd. All rights re served.