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 be en introduced as a potent and highly selective agonist of metabotropic glutamate (mGlu) receptor subtypes mGlu(2) and -(3). In murine cortic al cultures containing both neurons and astrocytes, 2R,4R-APDC attenua ted the delayed neuronal degeneration induced by a 10-min pulse of N-m ethyl-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 expressio n systems. The action of 2R,4R-APDC was sensitive to the mGlu(2/3) rec eptor antagonists, (2S)-alpha-ethylglutamate and ',3R')-2-(2'-carboxy- 3'-phenylcyclopropyl)glycine. These results indicate that activation o f mGlu(2) and/or -(3) receptors is sufficient per se to protect neuron s against excitotoxic degeneration, and encourage the search for poten t, selective and systemically active mGlu(2/3) receptor agonists as ne uroprotective drugs. (C) 1998 Elsevier Science B.V. All rights reserve d.