3-Nitropropionic acid: an astrocyte-sparing neurotoxin in vitro.
3-Nitropropionic acid (NPA), an inhibitor of succinate dehydrogenase, is dietary neurotoxin. It is not known if neurons and astrocytes differ in their vulnerability to NPA, therefore, we investigated its toxicity in primary cultures of cerebellar granule cells and astrocytes. NPA inhibited succinate dehydrogenase and tricarboxylic acid cycle activity to the same degree in neurons and astrocytes. Even so NPA acid was 16 times more toxic to neurons than to astrocytes (LC50: 0.7 and 11 mM, respectively). The neurotoxicity of NPA was mediated by NMDA-receptor activation, calcium influx, and formation of reactive oxygen species, as revealed by the protective effect of NMDA-receptor blockade, the accumulation of 45Ca, and the protective effect of N-t-butyl-alpha-phenylnitron (PBN), a scavenger of reactive oxygen species. Cytotoxic concentrations of NPA caused a reduction in the intracellular level of glutathione, which probably contributed to the oxidative damage in both neurons and astrocytes. The relative resistance of astrocytes to NPA appeared to be related to their low tricarboxylic acid cycle activity (5%-10% of that in neurons) and to the inability of NPA to cause astrocytic calcium overload. We conclude that NPA acid predominantly is an astrocyte-sparing neurotoxin.
Olsen
C
C
Norwegian Defence Research Establishment, Division for Environmental Toxicology, Kjeller, Norway.
Rustad
A
A
Fonnum
F
F
Paulsen
R E
RE
Hassel
B
B
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D003497:Cyclic N-Oxides; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009574:Nitro Compounds; D009589:Nitrogen Oxides / Q000494:pharmacology; D011422:Propionates / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000378:metabolism
D000596:Amino Acids; D003497:Cyclic N-Oxides; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D009498:Neurotoxins; D009574:Nitro Compounds; D009589:Nitrogen Oxides; D011422:Propionates; C029217:phenyl-N-tert-butylnitrone; D016291:Dizocilpine Maleate; D013385:Succinate Dehydrogenase; D005947:Glucose; C015392:3-nitropropionic acid; D002118:Calcium