Storgaard J, Kornblit B T, Zimmer J, Gramsbergen J B
Anatomy and Neurobiology, Institute of Medical Biology, Odense C, Denmark.
Exp Neurol. 2000 Jul;164(1):227-35. doi: 10.1006/exnr.2000.7428.
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.
3-硝基丙酸（3-NPA）对线粒体的抑制作用会导致纹状体变性，类似于亨廷顿舞蹈病。我们在器官型纹状体和皮质-纹状体切片培养物中研究了3-NPA的神经毒性以及可能的间接兴奋性毒性。通过检测培养基中的乳酸脱氢酶和组织匀浆中的谷氨酸脱羧酶来量化神经毒性。3-NPA的毒性（在含5 mM葡萄糖的培养基中为25 - 100 microM，作用24 - 48小时）似乎高度依赖于培养基中的葡萄糖水平。3-NPA处理还导致乳酸呈剂量依赖性增加，在100 microM时达到比对照高两倍的最大值。高剂量的谷氨酸（5 mM）以及dl-苏式-β-羟基天冬氨酸对谷氨酸摄取的阻断均增强了皮质-纹状体切片培养物中3-NPA的神经毒性。此外，皮质-纹状体共培养物中的纹状体对3-NPA比没有皮质的纹状体更敏感，并且河豚毒素、MK-801和d-2-氨基-5-磷酸戊酸可预防或减轻3-NPA的神经毒性，这表明谷氨酸能皮质-纹状体通路的膜去极化和/或神经元活动促成了纹状体病变。结果表明，3-NPA毒性的体内特征可在器官型皮质-纹状体切片培养物中重现。
