1-Aminoindan-1,5-dicarboxylic acid and (S)-(+)-2-(3'-carboxybicyclo[1.1.1] pentyl)-glycine, two mGlu1 receptor-preferring antagonists, reduce neuronal death in in vitro and in vivo models of cerebral ischaemia.
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.
Pellegrini-Giampietro
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DE
Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Italy. dompel@pharm.unifi.it
Cozzi
A
A
Peruginelli
F
F
Leonardi
P
P
Meli
E
E
Pellicciari
R
R
Moroni
F
F
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology; D001565:Benzoates / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000166:cytology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005849:Gerbillinae; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000473:pathology*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012118:Resorcinols / Q000494:pharmacology
C095756:1-aminoindan-1,5-dicarboxylic acid; D001565:Benzoates; D001643:Bridged Bicyclo Compounds; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011810:Quinoxalines; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; C100726:UPF 596; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C079694:alpha-methyl-4-carboxyphenylglycine; C079215:3,5-dihydroxyphenylglycine; D016291:Dizocilpine Maleate; D005998:Glycine