L-homocysteate is a potent neurotoxin on cultured cortical neurons.
L-Homocysteate (L-HCA) neurotoxicity was quantitatively studied in dissociated cell cultures prepared from the fetal mouse neocortex. Five minute exposure to 3 microM-1 mM L-HCA was associated with neuronal cell loss, but not glial cell loss; the extent of neuronal damage was dependent on the concentration of L-HCA, with an ED50 of approximately 40 microM. The stereoisomer D-HCA was a somewhat weaker neurotoxin than L-HCA. Ion substitution experiments suggested that L-HCA neurotoxicity can be separated into two components on the basis of differences in time course and ionic dependence: an acute, sodium-dependent 'excitotoxic' component, marked by rapid early cell swelling; and a late, calcium-dependent component, marked by delayed cell degeneration. L-HCA neurotoxicity could be attenuated by 2-amino-5-phosphonovalerate (APV), ketamine, and kynurenate, but not by L-glutamate diethyl ester or gamma-D-glutamylaminomethyl sulfonate, consistent with a predominant involvement of N-methyl-D-aspartate receptors. APV and ketamine produced different effects on the L-HCA concentration-toxicity relation, the former drug consistent with a competitive, and the latter drug consistent with a non-competitive, mechanism of antagonism.
Kim
J P
JP
Department of Neurology, Stanford University Medical Center, CA 94305.
Koh
J Y
JY
Choi
D W
DW
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D005110:Extracellular Space / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice / Q000196:embryology; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000494:pharmacology*; D009994:Osmolar Concentration; D012964:Sodium / Q000378:metabolism; D013997:Time Factors
D009498:Neurotoxins; D006710:Homocysteine; C007956:homocysteic acid; D001224:Aspartic Acid; D016202:N-Methylaspartate; D012964:Sodium; D002118:Calcium