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

摘要

Excessive release of glutamate during ischemia leads to sustained neuronal damage. In this study we investigated the influence of metabotropic glutamate receptor (mGluR) activation on neuronal recovery from a hypoxic/hypoglycemic event in hippocampal slices from rats. The slices were transiently exposed 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 spike amplitude recovered to 41.4% of baseline value within 1 h after hypoxia/hypoglycemia. The specific mGluR group I agonist 3,5-dihydroxyphenylglycine (DHPG, 10 microM) 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, when applied later, DHPG had no protective effect. Co-application of the protein kinase C (PKC) inhibitors staurosporine (100 nM) or chelerythrine (30 microM) 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 step of the protective mechanism.