upf-596 and 3-5-dihydroxyphenylglycine

Metabotropic glutamate (mGlu) receptors have been implicated in a number of physiological and pathological responses to glutamate, but the exact role of group I mGlu receptors in causing postischaemic injury is not yet clear. In this study, we examined whether the recently-characterized and relatively selective mGlu1 receptor antagonists 1-aminoindan-1,5-dicarboxylic acid (AIDA) and (S)-(+)-2-(3'-carboxybicyclo[1.1.1]pentyl)-glycine (CBPG) could reduce neuronal death in vitro, following oxygen-glucose deprivation (OGD) in murine cortical cell and rat organotypic hippocampal cultures, and in vivo, after global ischaemia in gerbils. When present in the incubation medium during the OGD insult and the subsequent 24 h recovery period, AIDA and CBPG significantly reduced neuronal death in vitro. The extent of protection was similar to that observed with the nonselective mGlu receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine [(+)MCPG] and with typical ionotropic glutamate (iGlu) receptor antagonists. Neuroprotection was also observed when AIDA or CBPG were added only after the OGD insult was terminated. Neuronal injury was not attenuated by the inactive isomer (-)MCPG, but was significantly enhanced by the nonselective mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1, 3-dicarboxylic acid [(1S,3R)-ACPD] and the group I mGlu receptor agonist 3,5-dihydroxyphenylglycine (3,5-DHPG). The antagonists (+)MCPG, AIDA and CBPG were also neuroprotective in vivo, because i. c.v. administration reduced CA1 pyramidal cell degeneration examined 7 days following transient carotid occlusion in gerbils. Our results point to a role of mGlu1 receptors in the pathological mechanisms responsible for postischaemic neuronal death and propose a new target for neuroprotection.

Topics: Animals; Animals, Newborn; Astrocytes; Benzoates; Bridged Bicyclo Compounds; Cell Death; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Gerbillinae; Glycine; Indans; Ischemic Attack, Transient; Mice; Neuroprotective Agents; Neurotoxins; Organ Culture Techniques; Pyramidal Cells; Quinoxalines; Receptors, Metabotropic Glutamate; Resorcinols

In the present study we used freely moving rats with a microdialysis probe placed in their parietal cortex to study the effects of local application of agonists and antagonists of metabotropic glutamate (mGlu) receptors on glutamate release. (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 0.1-1 mM), a non-selective agonist of metabotropic glutamate (mGlu) receptors, increased glutamate concentration in the dialysate up to 3-fold. A significant increase in glutamate output in cortical dialysates was also obtained with (RS)-3,5-dihydroxyphenylglycine (DHPG; 0.5-1 mM), a group 1-selective mGlu receptor agonist, suggesting the involvement of group 1 mGlu receptors in 1S,3R-ACPD effects. S-4-carboxyphenylglycine (S-4CPG; 0.3 microM), a mGlu1 receptor antagonist with a mild agonist action on mGlu2 receptors, antagonised, in a surmountable manner, the effects of 1S,3 R-ACPD. Similarly, 1-aminoindan-1,5-dicarboxylic acid (AIDA; 0.03-1 mM) a selective group 1 antagonist with a preferential action on mGlu1 type receptors, antagonised the effects of 1S,3R-ACPD. Finally, (S)-(+)-2-(3'-Carboxybicyclo[1.1.1]pentyl)-glycine (UPF596; 30-300 microM), a potent mGlu1 antagonist with modest agonist activity on mGlu5, antagonised 1S,3R-ACPD-induced glutamate release. In conclusion, our data showed that 1S,3R-ACPD-induced glutamate release in the parietal cortex is mediated by mGlu1 receptors and that, under basal conditions, these receptors are not tonically activated.

Topics: Animals; Benzoates; Bridged Bicyclo Compounds; Cycloleucine; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Indans; Microdialysis; Parietal Lobe; Rats; Receptors, Metabotropic Glutamate; Receptors, Presynaptic; Resorcinols