Selective activation of group II mGluRs with LY354740 does not prevent neuronal excitotoxicity

Neuropharmacology. 1999 Oct;38(10):1621-30. doi: 10.1016/s0028-3908(99)00098-2.

Abstract

Recent reports have suggested a role for group II metabotropic glutamate receptors (mGluRs) in the attenuation of excitotoxicity. Here we examined the effects of the recently available group II agonist (+)-2-Aminobicyclo[3.1.0]hexane-2-6-dicarboxylic acid (LY354740) on N-methyl-D-aspartate (NMDA)-induced excitotoxic neuronal death, as well as on hypoxic-ischemic neuronal death both in vitro and in vivo. At concentrations shown to be selective for group II mGluRs expressed in cell lines (0.1-100 nM), LY354740 did not attenuate NMDA-mediated neuronal death in vitro or in vivo. Furthermore, LY354740 did not attenuate oxygen-glucose deprivation-induced neuronal death in vitro or ischemic infarction after transient middle cerebral artery occlusion in rats. In addition, the neuroprotective effect of another group II agonist, (S)-4-carboxy-3-phenylglycine (4C3HPG), which has shown injury attenuating effects both in vitro and in vivo, was not blocked by the group II antagonists (2 S)-alpha-ethylglutamic acid (EGLU), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG), or the group III antagonist (S)-alpha-methyl-3-carboxyphenylalanine (MCPA), suggesting that this neuroprotection may be mediated by other effects such as upon group I mGluRs.

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / physiology*
  • Bridged Bicyclo Compounds / pharmacology*
  • CHO Cells
  • Cell Death / drug effects
  • Cell Hypoxia
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / physiology*
  • Cricetinae
  • Excitatory Amino Acid Agonists / pharmacology*
  • Glucose / metabolism
  • Ischemic Attack, Transient / physiopathology
  • Ischemic Attack, Transient / prevention & control
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • N-Methylaspartate / toxicity*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / physiology*
  • Neurotoxins / toxicity
  • Rats
  • Receptors, Metabotropic Glutamate / agonists
  • Receptors, Metabotropic Glutamate / physiology*
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Transfection

Substances

  • Bridged Bicyclo Compounds
  • Excitatory Amino Acid Agonists
  • Neurotoxins
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Glucose
  • eglumetad