3-Nitropropionic acid neurotoxicity in organotypic striatal and corticostriatal slice cultures is dependent on glucose and glutamate.
Mitochondrial inhibition by 3-nitropropionic acid (3-NPA) causes striatal degeneration reminiscent of Huntington's disease. We studied 3-NPA neurotoxicity and possible indirect excitotoxicity in organotypic striatal and corticostriatal slice cultures. Neurotoxicity was quantified by assay of lactate dehydrogenase in the medium and glutamic acid decarboxylase in tissue homogenates. 3-NPA toxicity (25-100 microM in 5 mM glucose, 24-48 h) appeared to be highly dependent on culture medium glucose levels. 3-NPA treatment caused also a dose-dependent lactate increase, reaching a maximum of threefold increase above control at 100 microM. Both a high dose of glutamate (5 mM) and glutamate uptake blockade by dl-threo-beta-hydroxyaspartate potentiated 3-NPA neurotoxicity in corticostriatal slice cultures. Furthermore, striatum from corticostriatal cocultures was more sensitive to 3-NPA than striatum without cortex and tetrodotoxin, MK-801, and d-2-amino-5-phosphonopentanoic acid prevented or attenuated 3-NPA neurotoxicity, suggesting that membrane depolarization and/or neuronal activity of the glutamatergic corticostriatal pathway contributes to striatal pathology. The results indicate that in vivo characteristics of 3-NPA toxicity can be reproduced in organotypic corticostriatal slice cultures.
Storgaard
J
J
Anatomy and Neurobiology, Institute of Medical Biology, Odense C, Denmark.
Kornblit
B T
BT
Zimmer
J
J
Gramsbergen
J B
JB
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D006816:Huntington Disease / Q000378:metabolism; D066298:In Vitro Techniques; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009574:Nitro Compounds; D011422:Propionates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors; D013779:Tetrodotoxin / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D009574:Nitro Compounds; D011422:Propionates; C011274:3-hydroxyaspartic acid; D001224:Aspartic Acid; D018698:Glutamic Acid; D013779:Tetrodotoxin; D013385:Succinate Dehydrogenase; D005968:Glutamate Decarboxylase; D005947:Glucose; C015392:3-nitropropionic acid