Neuroprotective activity of N-acetylaspartylglutamate in cultured cortical cells.
The endogenous dipeptide, alpha-N-acetylaspartylglutamate behaves as a partial agonist of N-methyl-D-aspartate receptors, but can also activate metabotropic glutamate receptors, with a high degree of selectivity for the metabotropic glutamate receptor 3 subtype. Knowing that agonists of group-II metabotropic glutamate receptors (i.e. of mGlu2 and -3 receptors) are neuroprotective, we have examined the neuroprotective activity of alpha-N-acetylaspartylglutamate in mixed cultures of mouse cortical cells exposed to a toxic pulse with N-methyl-D-aspartate. Alpha-N-acetylaspartylglutamate co-applied with N-methyl-D-aspartate was neuroprotective, but its action was insensitive to the selective group-II metabotropic glutamate receptor antagonist, ethylglutamate. Protection was instead antagonized by ethylglutamate when alpha-N-acetylaspartylglutamate was applied to the cultures immediately after the N-methyl-D-aspartate pulse, a condition in which there was no direct competition between alpha-N-acetylaspartylglutamate and N-methyl-D-aspartate at the level of N-methyl-D-aspartate receptors. alpha-N-acetylaspartylglutamate was highly neuroprotective when transiently applied to pure cultures of cortical astrocytes and the conditioned medium, collected 20 h later, was transferred to sister mixed cultures challenged with N-methyl-D-aspartate. This particular form of neuroprotection was attenuated or abolished when astrocytes where exposed to alpha-N-acetylaspartylglutamate in the presence of the group-II metabotropic glutamate receptor antagonists ethylglutamate or (2S, 1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine, but not in the presence of the N-methyl-D-aspartate receptor antagonist, D-2-amino-5-phosphonopentanoate. These results indicate that alpha-N-acetylaspartylglutamate induces neuroprotective effects in culture, which are mediated, at least in part, by the activation of glial metabotropic glutamate receptor 3 receptors.
Bruno
V
V
I.N.M. Neuromed, Pozzilli, Italy.
Wroblewska
B
B
Wroblewski
J T
JT
Fiore
L
L
Nicoletti
F
F
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003521:Cyclopropanes / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology
C099854:2-(2'-carboxy-3'-phenylcyclopropyl)glycine; D003521:Cyclopropanes; D004151:Dipeptides; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate; C017302:alpha-ethylglutamic acid; C078245:4-carboxy-3-hydroxyphenylglycine; C082313:2-(2,3-dicarboxycyclopropyl)glycine; C027172:isospaglumic acid; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D005998:Glycine