(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid attenuates N-methyl-D-aspartate-induced neuronal cell death in cortical cultures via a reduction in delayed Ca2+ accumulation.
The effects of (1S,3R)-ACPD, a selective metabotropic glutamate receptor agonist, on NMDA-induced 45Ca2+ accumulation and delayed neuronal cell death were determined using primary cerebrocortical cultures. Exposure to (1S,3R)-ACPD alone, although causing small increases in 45Ca2+ accumulation, was not neurotoxic. The presence of (1S,3R)-ACPD during exposure to NMDA attenuated the resulting sustained accumulation of 45Ca2+ and delayed neuronal cell death. Reductions in sustained Ca2+ accumulation were associated both with Ca2+ efflux, in the absence of cell death, and inhibition of delayed intracellular Ca2+ accumulation. The protective effects of (1S,3R)-ACPD on NMDA-induced cell death were inhibited by pretreatment of cultures with pertussis toxin. These results suggest that activation of metabotropic glutamate receptors may stimulate intracellular processes capable of limiting sustained elevations in intracellular calcium and the resulting excitotoxic neuronal damage.
Birrell
G J
GJ
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, MI 48106-1047.
Gordon
M P
MP
Marcoux
F W
FW
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism*; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005333:Fetus; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D005971:Glutamates; D009498:Neurotoxins; D010716:Phosphatidylinositols; D010566:Virulence Factors, Bordetella; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D018698:Glutamic Acid; D016202:N-Methylaspartate; D007770:L-Lactate Dehydrogenase; D037342:Pertussis Toxin; D002118:Calcium