Inhibition of fatty acid beta-oxidation in rat brain cultured astrocytes exposed to the neurotoxin 3-nitropropionic acid.
We describe the effects of the neurotoxin 3-nitropropionic acid (3-NPA) on fatty acid oxidation in neonatal rat brain astrocytes in primary culture, using a sensitive assay for beta-oxidation which depends on the release of 3H2O from [9,10(n)-3H]palmitic acid. 3-NPA is a suicide inhibitor of succinate dehydrogenase, a constituent of both Krebs cycle and complex II of the mitochondrial respiratory chain. It is widely distributed in plants and fungi. Neurotoxicity of 3-NPA to humans and animals, leading to selective neuronal cell death, appears mediated by the reduced level of ATP induced by the toxin. We demonstrated that 3-NPA can also impair energy metabolism in astrocytes. Exposure of astroglial cells in culture to 3-NPA leads to inhibition of the release of 3H2O from [9,10(n)-3H]palmitic acid. Addition of 2 mM 3-NPA to the culture medium caused a rapid decrease in beta-oxidation activity, which reached a plateau after 90 min. This inhibition was concentration-dependent. Concentration as low as 0.05 mM for 5 h significantly decreased beta-oxidation activity (25% inhibition). Half-maximal inhibition was obtained after treatment with 0.5 mM 3-NPA, and 3 mM induced a maximal response (63% inhibition) 3-NPA is clearly a potent inhibitor of beta-oxidation activity. We also show that 3-NPA 3 mM inhibits partially complex II (succinate ubiquinone reductase) and aspartate aminotransferase by 60 and 49% after 4 h treatment respectively. It has been shown that fatty acid is the preferred substrate for energy production in cultured astrocytes from developing brain. As astrocytes may also provide substrates alternative for energy metabolism in neurons and oligodendrocytes, it is likely that the inhibition of beta-oxidation by 3-NPA may contribute significantly to the damage induced by this toxin in the central nervous system.
Esfandiari
A
A
INSERM Unité 134, CNRS SDI, Hôpital de la Salpĕtrière, Paris, France.
Soifiyoudine
D
D
Paturneau-Jouas
M
M
D000818:Animals; D001219:Aspartate Aminotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002331:Carnitine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009498:Neurotoxins / Q000494:pharmacology*; D009574:Nitro Compounds; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D051381:Rats
D005227:Fatty Acids; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D019308:Palmitic Acid; D001219:Aspartate Aminotransferases; C015392:3-nitropropionic acid; D002331:Carnitine