Williams R E, Jones P, Lock E A, Bachelard H S
Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, England.
J Neurochem. 1999 Jul;73(1):362-71. doi: 10.1046/j.1471-4159.1999.0730362.x.
L-2-Chloropropionic acid (L-CPA) is selectively toxic to cerebellar granule cells; necrosis is first observed in rats 36 h after L-CPA administration (750 mg/kg p.o.) and becomes marked by 48 h. L-CPA has also been shown to activate the mitochondrial pyruvate dehydrogenase (PDH) complex in fasted adult rats, resulting in reduced blood glucose and lactate levels. This study aimed to investigate the biochemical and neurotoxicological effects of L-CPA on the brain. Extracts, prepared from guinea-pig cerebellar and cerebral cortex slices incubated in the presence of L-CPA, were analysed using 1H magnetic resonance spectroscopy, 31P magnetic resonance spectroscopy, and amino acid analysis. Glucose metabolism was studied by monitoring the metabolism of [1-(13)C]glucose using gas chromatography/mass spectrometry. Increased glucose metabolism and decreases in the pool sizes of lactate and alanine were observed in both tissues, demonstrating activation of the PDH complex. Extracts were also prepared from the forebrain and cerebellum of animals that had been treated in vivo with L-CPA and analysed as described for the in vitro studies. Similar evidence for PDH activation was demonstrated at 2 and 24 h after dosing in both tissues. At 48 h after dosing, when signs of toxicity are observed, an increase in the lactate concentration and a decrease in N-acetylaspartate in the cerebellum but not in the forebrain confirmed the selective neurotoxic action of L-CPA. These results suggest that activation of the PDH complex does not directly lead to the delayed selective neurotoxicity of L-CPA.
L-2-氯丙酸（L-CPA）对小脑颗粒细胞具有选择性毒性；在给大鼠口服L-CPA（750mg/kg）后36小时首次观察到坏死，48小时时坏死明显。L-CPA还被证明可激活禁食成年大鼠的线粒体丙酮酸脱氢酶（PDH）复合物，导致血糖和乳酸水平降低。本研究旨在探讨L-CPA对大脑的生化和神经毒理学影响。使用1H磁共振波谱、31P磁共振波谱和氨基酸分析对在L-CPA存在下孵育的豚鼠小脑和大脑皮质切片制备的提取物进行分析。通过使用气相色谱/质谱监测[1-(13)C]葡萄糖的代谢来研究葡萄糖代谢。在两种组织中均观察到葡萄糖代谢增加以及乳酸和丙氨酸池大小减小，表明PDH复合物被激活。还从体内用L-CPA处理过的动物的前脑和小脑中制备提取物，并按照体外研究的方法进行分析。在给药后2小时和24小时，在两种组织中均证实了PDH激活的类似证据。在给药后48小时，当观察到毒性迹象时，小脑中乳酸浓度增加而N-乙酰天门冬氨酸减少，而前脑中未出现这种情况，这证实了L-CPA的选择性神经毒性作用。这些结果表明，PDH复合物的激活并不直接导致L-CPA延迟的选择性神经毒性。
