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 t he release of (H2O)-H-3 from [9,10(n)-H-3]palmitic acid. 3-NPA is a su icide inhibitor of succinate dehydrogenase, a constituent of both Kreb s cycle and complex II of the mitochondrial respiratory chain. It is w idely distributed in plants and fungi. Neurotoxicity of 3-NPA to human s and animals, leading to selective neuronal cell death, appears media ted by the reduced level of ATP induced by the toxin. We demonstrated that 3-NPA can also impair energy metabolism in astrocytes. Exposure o f astroglial cells in culture to 3-NPA leads to inhibition of the rele ase of (H2O)-H-3 from [9,10(n)-H-3]palmitic acid. Addition of 2 mM 3-N PA to the culture medium caused a rapid decrease in beta-oxidation act ivity, which reached a plateau after 90 min. This inhibition was conce ntration-dependent. Concentration as low as 0.05 mM for 5 h significan tly decreased beta-oxidation activity (25% inhibition). Half-maximal i nhibition was obtained after treatment with 0.5 mM 3-NPA, and 3 mM ind uced a maximal response (63% inhibition). 3-NPA is clearly a potent in hibitor of beta-oxidation activity. We also show that 3-NPA 3 mM inhib its partially complex II (succinate ubiquinone reductase) and aspartat e aminotransferase by 60 and 49% after 3 h treatment respectively. It has been shown that fatty acid is the preferred substrate for energy p roduction in cultured astrocytes from developing brain. As astrocytes may also provide substrate alternative for energy metabolism in neuron s and oligodendrocytes, it is likely that the inhibition of beta-oxida tion by 3-NPA may contribute significantly to the damage induced by th is toxin in the central nervous system.