Tsai M J, Goh C C, Wan Y L, Chang C
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China.
Neuroscience. 1997 Aug;79(3):819-26. doi: 10.1016/s0306-4522(97)00015-8.
Quantitative high resolution in vitro 1H nuclear magnetic resonance spectroscopy was employed to study the metabolic effects of 3-nitropropionic acid associated with aging from perchloric acid extracts of rat striata. Systemic injection of 3-nitropropionic acid in rats at a dose of 10 mg/kg/day for seven consecutive days significantly impaired energy metabolism in rats one, four and eight months of age, as evidenced by a marked elevation of succinate and lactate levels. However, a significant decrease in N-acetyl-L-aspartate level, a neuronal marker, was observed in four- and eight-month-old rats but not in one-month-old rats. This would indicate that rats at four to eight months are more susceptible to 3-nitropropionic acid than those at one month. A significant decrease in GABA level was observed in four-month-old 3-nitropropionic acid-treated rats, which is consistent with the literature that GABAergic neurons are particularly vulnerable to 3-nitropropionic acid treatment. In addition, glutamine and glutamate levels were markedly decreased at four and eight months in 3-nitropropionic acid-treated rats. Since glutamine is synthesized predominantly in glia, the observation above suggests that 3-nitropropionic acid intoxication may involve perturbation of energy metabolism, glial injury and consequent neuronal damage. Astrocytes which are essential in the metabolism of glutamate and glutamine were used to further assess 3-nitropropionic acid-induced toxicity. Glial proliferation, mitochondrial metabolism and glutamine synthetase activity were all reduced by 3-nitropropionic acid treatment with a concomitant increase, in a dose-dependent manner, of lactate levels, suggesting that 3-nitropropionic acid is also detrimental to astrocytes in vivo and thus may affect metabolic interaction between neurons and glia. These results not only imply that 3-nitropropionic acid blocks energy metabolism prior to exerting neurotoxic damage but also demonstrate that the degree of energy depletion determines the detrimental effects of 3-nitropropionic acid. In the present study, we also demonstrate that glutamate and glutamine levels as well as astrocytic functions may play pivotal roles in 3-nitropropionic acid-induced striatal lesions.
采用定量高分辨率体外¹H核磁共振波谱法，研究大鼠纹状体高氯酸提取物中与衰老相关的3-硝基丙酸的代谢效应。连续7天以10mg/kg/天的剂量给大鼠全身注射3-硝基丙酸，显著损害了1、4和8月龄大鼠的能量代谢，琥珀酸和乳酸水平显著升高证明了这一点。然而，在4和8月龄大鼠中观察到神经元标志物N-乙酰-L-天冬氨酸水平显著降低，而在1月龄大鼠中未观察到。这表明4至8月龄的大鼠比1月龄的大鼠对3-硝基丙酸更敏感。在4月龄经3-硝基丙酸处理的大鼠中观察到GABA水平显著降低，这与文献报道一致，即GABA能神经元特别容易受到3-硝基丙酸处理的影响。此外，在经3-硝基丙酸处理的大鼠中，4和8月龄时谷氨酰胺和谷氨酸水平显著降低。由于谷氨酰胺主要在神经胶质细胞中合成，上述观察结果表明，3-硝基丙酸中毒可能涉及能量代谢紊乱、神经胶质细胞损伤及随之而来的神经元损伤。对在谷氨酸和谷氨酰胺代谢中起重要作用的星形胶质细胞进行进一步评估，以研究3-硝基丙酸诱导的毒性。3-硝基丙酸处理降低了神经胶质细胞增殖、线粒体代谢和谷氨酰胺合成酶活性，同时乳酸水平以剂量依赖性方式升高，这表明3-硝基丙酸在体内对星形胶质细胞也有害，因此可能影响神经元与神经胶质细胞之间的代谢相互作用。这些结果不仅意味着3-硝基丙酸在造成神经毒性损伤之前会阻断能量代谢，而且还表明能量消耗程度决定了3-硝基丙酸的有害作用。在本研究中，我们还证明谷氨酸和谷氨酰胺水平以及星形胶质细胞功能可能在3-硝基丙酸诱导的纹状体损伤中起关键作用。
