Chih C P, He J, Sly T S, Roberts E L
Geriatric Research, Education, and Clinical Center, and Research Office, Miami VA Medical Center, Miami, FL 33125, USA.
Brain Res. 2001 Mar 2;893(1-2):143-54. doi: 10.1016/s0006-8993(00)03306-0.
It has been postulated that lactate released from astrocytes may be the preferred metabolic substrate for neurons, particularly during intense neuronal activity (the astrocyte-neuron lactate shuttle hypothesis). We examined this hypothesis by exposing rat hippocampal slices to artificial cerebrospinal fluid containing either glucose or lactate and either N-methyl-D-aspartate, which activates neurons without stimulating astrocytic glucose uptake, or alpha-cyano-4-hydroxycinnamate, which blocks monocarboxylate transport across plasma and mitochondrial membranes. When exposed to N-methyl-D-aspartate, slices lost synaptic transmission and K+ homeostasis more slowly in glucose-containing artificial cerebrospinal fluid than in lactate-containing artificial cerebrospinal fluid. After N-methyl-D-aspartate exposure, slices recovered synaptic transmission more completely in glucose. These results suggest that hippocampal neurons can use glucose more effectively than lactate when energy demand is high. In experiments with alpha-cyano-4-hydroxycinnamate, 500 microM alpha-cyano-4-hydroxycinnamate caused loss of K+ homeostasis and synaptic transmission in hippocampal slices during normoxia. When 200 microM alpha-cyano-4-hydroxycinnamate was used, synaptic activity and intracellular pH in slices decreased significantly during normoxia. These results suggest that alpha-cyano-4-hydroxycinnamate may have blocked mitochondrial oxidative metabolism along with lactate transport. Thus, studies using alpha-cyano-4-hydroxycinnamate to demonstrate the presence of a lactate shuttle in the brain tissue may need reevaluation. Our findings, together with observations in the literature that (1) glucose is available to neurons during activation, (2) heightened energy demand rapidly activates glycolysis in neurons, and (3) activation of glycolysis suppresses lactate utilization, suggests that glucose is the primary substrate for neurons during neuronal activation and do not support the astrocyte-neuron lactate shuttle hypothesis.
据推测，星形胶质细胞释放的乳酸可能是神经元的首选代谢底物，尤其是在神经元活动强烈时（星形胶质细胞-神经元乳酸穿梭假说）。我们通过将大鼠海马切片暴露于含有葡萄糖或乳酸的人工脑脊液中，并分别加入能激活神经元而不刺激星形胶质细胞摄取葡萄糖的N-甲基-D-天冬氨酸，或能阻断单羧酸跨质膜和线粒体膜转运的α-氰基-4-羟基肉桂酸，来检验这一假说。当暴露于N-甲基-D-天冬氨酸时，与含有乳酸的人工脑脊液相比，含有葡萄糖的人工脑脊液中的切片失去突触传递和钾离子稳态的速度更慢。在暴露于N-甲基-D-天冬氨酸后，切片在葡萄糖中恢复突触传递更完全。这些结果表明，当能量需求较高时，海马神经元利用葡萄糖比利用乳酸更有效。在用α-氰基-4-羟基肉桂酸进行的实验中，500微摩尔的α-氰基-4-羟基肉桂酸在常氧条件下导致海马切片中钾离子稳态丧失和突触传递消失。当使用200微摩尔的α-氰基-4-羟基肉桂酸时，切片在常氧条件下的突触活动和细胞内pH值显著降低。这些结果表明，α-氰基-4-羟基肉桂酸可能在阻断乳酸转运的同时也阻断了线粒体氧化代谢。因此，使用α-氰基-4-羟基肉桂酸来证明脑组织中存在乳酸穿梭的研究可能需要重新评估。我们的研究结果，连同文献中的观察结果，即（1）激活期间神经元可获得葡萄糖，（2）能量需求增加会迅速激活神经元中的糖酵解，以及（3）糖酵解激活会抑制乳酸利用，表明在神经元激活期间葡萄糖是神经元的主要底物，并不支持星形胶质细胞-神经元乳酸穿梭假说。
