Selective activation of group-II metabotropic glutamate receptors is protective against excitotoxic neuronal death

Aminopyrrolidine-2 R,4 R-dicarboxylated (2 R,4 R-APDC) has recently been introduced as a potent and highly selective agonist of metabotropic glutamate (mGlu) receptor subtypes mGlu(2) and -(3). In murine cortical cultures containing both neurons and astrocytes, 2R,4R-APDC attenuated the delayed neuronal degeneration induced by a 10-min pulse of N-methyl-D-aspartate (NMDA). 2R,4R-APDC was maximally neuroprotective in a range of concentrations (0.1-1 mu M) comparable to that reported for the activation of mGlu(2) or -(3) receptors in heterologous expression systems. The action of 2R,4R-APDC was sensitive to the mGlu(2/3) receptor antagonists, (2S)-alpha-ethylglutamate and (2S,1S',2S',3R')-2-(2'-carboxy-3'-phenylcyclopropyl)glycine. These results indicate that activation of mGlu(2) and/or -(3) receptors is sufficient per se to protect neurons against excitotoxic degeneration, and encourage the search for potent, selective and systemically active mGlu(2/3) receptor agonists as neuroprotective drugs. (C) 1998 Elsevier Science B.V. All rights reserved.