Esfandiari A, Soifiyoudine D, Paturneau-Jouas M
INSERM Unité 134, CNRS SDI, Hôpital de la Salpĕtrière, Paris, France.
Dev Neurosci. 1997;19(4):312-20. doi: 10.1159/000111227.
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.
我们使用一种依赖于[9,10(n)-3H]棕榈酸释放3H2O的β-氧化敏感检测方法，描述了神经毒素3-硝基丙酸（3-NPA）对原代培养新生大鼠脑星形胶质细胞脂肪酸氧化的影响。3-NPA是琥珀酸脱氢酶的自杀性抑制剂，琥珀酸脱氢酶是三羧酸循环和线粒体呼吸链复合体II的组成部分。它广泛分布于植物和真菌中。3-NPA对人和动物的神经毒性导致选择性神经元细胞死亡，似乎是由该毒素诱导的ATP水平降低介导的。我们证明3-NPA也会损害星形胶质细胞的能量代谢。将培养的星形胶质细胞暴露于3-NPA会导致[9,10(n)-3H]棕榈酸释放3H2O受到抑制。向培养基中添加2 mM 3-NPA会导致β-氧化活性迅速下降，90分钟后达到平台期。这种抑制作用呈浓度依赖性。低至0.05 mM处理5小时可显著降低β-氧化活性（抑制25%）。用0.5 mM 3-NPA处理后获得半数最大抑制，3 mM诱导最大反应（抑制63%）。3-NPA显然是β-氧化活性的有效抑制剂。我们还表明，3 mM 3-NPA分别在处理4小时后对复合体II（琥珀酸泛醌还原酶）和天冬氨酸转氨酶的抑制率为60%和49%。已经表明，脂肪酸是发育中脑培养的星形胶质细胞产生能量的首选底物。由于星形胶质细胞也可能为神经元和少突胶质细胞的能量代谢提供替代底物，3-NPA对β-氧化的抑制很可能对该毒素在中枢神经系统中引起的损伤有显著贡献。
