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

Aminopyrrolidine-2R,4R-dicarboxylated (2R,4R-APDC) has recently been introduced as a potent and highly selective agonist of metabotropic glutamate (mGlu) receptor subtypes mGlu2 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 μM) comparable to that reported for the activation of mGlu2 or -3 receptors in heterologous expression systems. The action of 2R,4R-APDC was sensitive to the mGlu(2/3) receptor antagonists, (2S)-α-ethylglutamate and (2S,1S',2S',3R')-2-(2'-carboxy-3'-phenylcyclopropyl)glycine. These results indicate that activation of mGlu2 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.