Massieu L, Haces M L, Montiel T, Hernández-Fonseca K
Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, CP 04510, AP 70-253, Mexico D.F., Mexico.
Neuroscience. 2003;120(2):365-78. doi: 10.1016/s0306-4522(03)00266-5.
Glucose is the main substrate that fulfills energy brain demands. However, in some circumstances, such as diabetes, starvation, during the suckling period and the ketogenic diet, brain uses the ketone bodies, acetoacetate and beta-hydroxybutyrate, as energy sources. Ketone body utilization in brain depends directly on its blood concentration, which is normally very low, but increases substantially during the conditions mentioned above. Glutamate neurotoxicity has been implicated in neurodegeneration associated with brain ischemia, hypoglycemia and cerebral trauma, conditions related to energy failure, and to elevation of glutamate extracellular levels in brain. In recent years substantial evidence favoring a close relation between glutamate neurotoxic potentiality and cellular energy levels, has been compiled. We have previously demonstrated that accumulation of extracellular glutamate after inhibition of its transporters, induces neuronal death in vivo during energy impairment induced by glycolysis inhibition. In the present study we have assessed the protective potentiality of the ketone body, acetoacetate, against glutamate-mediated neuronal damage in the hippocampus of rats chronically treated with the glycolysis inhibitor, iodoacetate, and in hippocampal cultured neurons exposed to a toxic concentration of iodoacetate. Results show that acetoacetate efficiently protects against glutamate neurotoxicity both in vivo and in vitro probably by a mechanism involving its role as an energy substrate.
葡萄糖是满足大脑能量需求的主要底物。然而，在某些情况下，如糖尿病、饥饿、哺乳期和生酮饮食期间，大脑会利用酮体（乙酰乙酸和β-羟基丁酸）作为能量来源。大脑中酮体的利用直接取决于其血液浓度，该浓度通常很低，但在上述情况下会大幅增加。谷氨酸神经毒性与脑缺血、低血糖和脑外伤相关的神经退行性变有关，这些情况与能量衰竭以及大脑中谷氨酸细胞外水平升高有关。近年来，大量证据表明谷氨酸神经毒性潜力与细胞能量水平之间存在密切关系。我们之前已经证明，抑制谷氨酸转运体后细胞外谷氨酸的积累，会在糖酵解抑制诱导的能量损伤期间在体内诱导神经元死亡。在本研究中，我们评估了酮体乙酰乙酸对长期用糖酵解抑制剂碘乙酸处理的大鼠海马体以及暴露于毒性浓度碘乙酸的海马体培养神经元中谷氨酸介导的神经元损伤的保护潜力。结果表明，乙酰乙酸可能通过其作为能量底物的作用机制，在体内和体外均能有效保护神经元免受谷氨酸神经毒性的影响。
