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 microM) 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 mGlu2/3 receptor antagonists, (2S)-alpha-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 mGlu2/3 receptor agonists as neuroprotective drugs.
Battaglia
G
G
I.N.M. Neuromed, Pozzilli, Italy.
Bruno
V
V
Ngomba
R T
RT
Di Grezia
R
R
Copani
A
A
Nicoletti
F
F
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors
C097299:4-aminopyrrolidine-2,4-dicarboxylic acid; D018690:Excitatory Amino Acid Agonists; D018094:Receptors, Metabotropic Glutamate; D016202:N-Methylaspartate; D011392:Proline