Inhibition of evoked glutamate release by the neuroprotective 5-HT1A receptor agonist BAY x 3702 in vitro and in vivo

Brain ischemia provoked by stroke or traumatic brain injury induces a massi ve increase in neurotransmitter release, in particular of the excitotoxin g lutamate. Glutamate triggers a cascade of events finally leading to widespr ead neuronal cell damage and death. The aminomethylchroman derivative BAY x 3702 is a novel neuroprotectant which shows pronounced beneficial effects in various animal models of ischemic brain injury. As shown previously BAY x 3702 binds to 5-HT1A receptors of different species in subnanomolar range and is characterized as a full receptor agonist. In this study we investig ated the influence of BAY x 3702 on potassium-evoked glutamate release in v itro and ischemia-induced glutamate release in vivo. In rat hippocampal sli ces BAY x 3702 inhibited evoked glutamate release in a dose-dependent manne r (IC50 = 1 muM). This effect was blocked by the selective 5-HT1A receptor antagonist WAY 100635, indicating that BAY x 3702 specifically acts via 5-H T1A receptors. In vivo, release of endogenous aspartate and glutamate was m easured in the cortex of rats by microdialysis before and after onset of pe rmanent middle cerebral artery occlusion. Single dose administration of BAY x 3702 (1 mug/kg or 10 mug/kg i.v.) immediately after occlusion reduced th e increase and total release of extracellular glutumate by about 50% compar ed to non-treated animals, whereas the extracellular aspartate levels were not significantly affected. Inhibition of glutamate release may therefore c ontribute to the pronounced neuroprotective efficacy of BAY x 3702 in vario us animal models of ischemic brain damage. (C) 2001 Elsevier Science B.V. A ll rights reserved.