Activation of metabotropic glutamate receptors protects cultured neurons against apoptosis induced by beta-amyloid peptide.
Prolonged exposure of cultured cortical cells or cultured cerebellar granule cells to the residue 25-35 fragment of beta-amyloid peptide (beta AP), beta AP(25-35), induced neuronal apoptosis, as revealed by morphological analysis, fluorescent chromatin staining, and immunodetection of oligonucleosomes released from the nucleus into the cytoplasm. beta AP(25-35)-induced apoptosis was insensitive to ionotropic glutamate receptor antagonists but was substantially attenuated by the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. The neuroprotective action of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid was antagonized by (RS)-alpha-methyl-4-carboxyphenylglycine and was mimicked by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (a selective agonist of mGluR2 and -3 subtypes) and by L-2-amino-4-phosphobutanoate and L-serine-O-phosphate (selective agonists of mGluR4, -6, and -7 subtypes). However, whereas all of these drugs behaved as neuroprotectants in cultured cortical cells, only L-2-amino-4-phosphobutanoate and L-serine-O-phosphate [and not (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine] reduced beta AP(25-35)-induced apoptosis in cultured cerebellar granule cells. The neuroprotective activity of mGluR agonists may be related to their ability to inhibit membrane Ca2+ conductance, because drugs that block voltage-sensitive Ca2+ channels, such as nimodipine or Co2+, could also attenuate beta AP(25-35)-induced apoptosis.
Copani
A
A
Institute of Pharmacology, University of Catania, Italy.
Bruno
V
V
Battaglia
G
G
Leanza
G
G
Pellitteri
R
R
Russo
A
A
Stanzani
S
S
Nicoletti
F
F
D000613:Aminobutyrates / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001565:Benzoates / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D009410:Nerve Degeneration / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000633:toxicity; D010768:Phosphoserine / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*
D000613:Aminobutyrates; D016229:Amyloid beta-Peptides; D001565:Benzoates; D015220:Calcium Channels; D010446:Peptide Fragments; D018094:Receptors, Metabotropic Glutamate; C074636:amyloid beta-protein (25-35); D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C079694:alpha-methyl-4-carboxyphenylglycine; D010768:Phosphoserine; C012729:2-amino-4-phosphonobutyric acid; D005998:Glycine