Effects of t-ACPD on neural survival and second messengers in cultured cerebral cortical neurones.
The cytotoxic potential of (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (t-ACPD) in cultured murine cerebral cortical neurones was examined. Exposure to t-ACPD (1 mM, 16 h) did not induce cytotoxicity per se or affect N-methyl-D-aspartate-induced toxicity. Phosphoinositide hydrolysis was weakly stimulated by t-ACPD (1 mM), while no alteration of intracellular calcium levels was observed after exposure to 1 mM t-ACPD. However, forskolin-stimulated cAMP formation was inhibited by t-ACPD (IC50 = 8 +/- 2 microM) with a maximal inhibition of 36 +/- 4% of control levels. These data suggest that the lack of neurotoxic effects of t-ACPD may be related to the negligible efficacy of t-ACPD to activate mGluRs coupled to the IP3/Ca(2+)-cascade and/or putative counteracting effects of t-ACPD mediated by mGluRs negatively coupled to the cAMP-cascade.
Thomsen
C
C
Novo Nordisk A/S, Pharmaceuticals Division, Måløv, Denmark.
Frandsen
A
A
Suzdak
P D
PD
Andersen
C F
CF
Schousboe
A
A
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D005576:Colforsin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006868:Hydrolysis; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D015290:Second Messenger Systems / Q000187:drug effects*
D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D005576:Colforsin; D016202:N-Methylaspartate; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D002118:Calcium