Loubinoux I, Meric P, Borredon J, Correze J L, Gillet B, Beloeil J C, Tiffon B, Mispelter J, Lhoste J M, Jacques S
Laboratoire de Recherches Cérébrovasculaires, CNRS UA 641, Centre Universitaire Villemin, Université Paris VII, France.
Brain Res. 1994 Apr 18;643(1-2):115-24. doi: 10.1016/0006-8993(94)90016-7.
The dynamic effects of the non-competitive NMDA receptor antagonist, MK-801 on brain metabolism were investigated over 105 minutes in unanesthetized rats by proton and phosphorus NMR spectroscopy. MK-801 (0.5 and 5 mg/kg, i.p) induced no changes in intracellular pH, and in phosphocreatine, ATP, and inorganic phosphate levels, indicating that the drug preserved energy and intracellular pH homeostasis. There were transient increases in lactate after both doses of MK-801, suggesting early activation of glycolysis, which was not immediately matched by enhanced oxidative metabolism or by enhanced blood flow. Thereafter, lactate control level was not restored after 0.5 mg/kg whereas it was restored after 5 mg/kg in spite of a sustained metabolic activation. The low dose of MK-801 also caused a continuous decrease in cerebral aspartate level (-38%) which is thought to match the enhanced energy demand, whereas the high dose caused shorter and smaller changes. The intracerebral glucose level rose after MK-801 injection, indicating that brain tissue had an adequate or even excessive supply of glucose. Glucose time course seemed to closely match the changes in blood flow elicited by MK-801. This is the first study giving the metabolic pattern of a pharmacological activation. We demonstrate an excess of glycolysis over oxidative metabolism in the early time similar to that following physiological and pathophysiological states such as photic stimulation and seizures. The difference between the effects of the two doses of MK-801 suggests that the adjustment of cerebral metabolism to MK-801 activation is faster and greater with the high dose than with the low dose.
通过质子和磷核磁共振波谱法，在105分钟内研究了非竞争性NMDA受体拮抗剂MK-801对未麻醉大鼠脑代谢的动态影响。腹腔注射0.5和5mg/kg的MK-801未引起细胞内pH值、磷酸肌酸、ATP和无机磷酸盐水平的变化，表明该药物维持了能量和细胞内pH值的稳态。两种剂量的MK-801给药后乳酸均出现短暂升高，提示糖酵解早期激活，但氧化代谢增强或血流增加并未与之立即匹配。此后，0.5mg/kg剂量给药后乳酸控制水平未恢复，而5mg/kg剂量给药后尽管代谢持续激活，但乳酸控制水平恢复。低剂量的MK-801还导致脑内天冬氨酸水平持续下降（-38%），这被认为与能量需求增加相匹配，而高剂量引起的变化持续时间更短且幅度更小。MK-801注射后脑内葡萄糖水平升高，表明脑组织有充足甚至过量的葡萄糖供应。葡萄糖的时间进程似乎与MK-801引起的血流变化密切匹配。这是第一项给出药理激活代谢模式的研究。我们证明，在早期，糖酵解超过氧化代谢，类似于光刺激和癫痫等生理和病理生理状态后的情况。两种剂量的MK-801作用效果的差异表明，高剂量比低剂量时，脑代谢对MK-801激活的调节更快且幅度更大。
