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

Abstract

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, 2 R,4 R-APDC attenuated the delayed neuronal degeneration induced by a 10-min pulse of N-methyl- d-aspartate (NMDA). 2 R,4 R-APDC was maximally neuroprotective in a range of concentrations (0.1–1 μM) comparable to that reported for the activation of mGlu 2 or - 3 receptors in heterologous expression systems. The action of 2 R,4 R-APDC was sensitive to the mGlu 2/3 receptor antagonists, (2 S)-α-ethylglutamate and (2 S,1 S′,2 S′,3 R′)-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.