Protection with metabotropic glutamate 1 receptor antagonists in models ofischemic neuronal death: time-course and mechanisms

In order to study the role of metabotropic glutamate 1 (mGlu1) receptors in ischemic neuronal death, we examined the effects of the recently character ized and relatively selective mGlu1 receptor antagonists 1-aminoindan-1,5-d icarboxylic acid (AIDA) and (S)-( +)-2-(3'-carboxybicyclo[1.1.1]pentyl)-gly cine (CBPG) in murine cortical cell cultures and rat organotypic hippocampa l slices exposed to oxygen-glucose deprivation (OGD) and in vivo, following transient global ischemia in gerbils. AIDA and CBPG significantly reduced neuronal death when added to the incubation medium during the OGD insult an d the subsequent recovery period. Neuroprotection was observed even when th ese compounds were added up to 60 min (in cortical neurons) or 30 min (in h ippocampal slices) after OGD. In vivo, i.c.v. administration of AIDA and CB PG reduced hippocampal CAI pyramidal cell injury following transient global ischemia. Neuroprotection was also observed when AIDA was added to the hip pocampal perfusion fluid in microdialysis experiments, and this effect was associated with an increase in the basal output of GABA. These findings dem onstrate that AIDA and CBPG are neuroprotective when administered during th e maturation of ischemic damage and that different mechanisms are likely to be involved in mediating their effects following blockade of mGlu1 recepto rs in cortical and hippocampal neurons. (C) 1999 Elsevier Science Ltd. All rights reserved.