Thurston J H, Hauhart R E
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, Missouri 63110.
Life Sci. 1989;45(1):59-62. doi: 10.1016/0024-3205(89)90435-9.
We have previously reported that chronic administration of valproate in developing mice decreased brain aspartic and glutamic acid levels and increased the brain taurine content. The direction of the valproate-induced changes in the cerebral levels of these neurotransmitter amino acids - excitatory in the case of aspartate and glutamate, inhibitory in the case of taurine - appeared relevant to the mechanism of its anticonvulsant action. Since the neuropathology of hypoxia-ischemia also appears to be mediated by release of glutamate/aspartate at the synapse, the valproate-induced reduction of the levels of these neuroexcitatory/neurotoxic amino acids suggested that valproate might increase the tolerance of young mice to anoxia. A doubling of the length of survival of the intact animal in an atmosphere of pure nitrogen gas and a three-fold increase in the duration of respiratory activity (gasping) of the isolated head after chronic administration of valproate support the speculation.
我们之前曾报道，在发育中的小鼠中长期给予丙戊酸盐会降低脑内天冬氨酸和谷氨酸水平，并增加脑内牛磺酸含量。丙戊酸盐诱导的这些神经递质氨基酸脑内水平变化的方向——天冬氨酸和谷氨酸为兴奋性，牛磺酸为抑制性——似乎与其抗惊厥作用机制相关。由于缺氧缺血的神经病理学似乎也由突触处谷氨酸/天冬氨酸的释放介导，丙戊酸盐诱导的这些神经兴奋性/神经毒性氨基酸水平降低表明，丙戊酸盐可能会增加幼鼠对缺氧的耐受性。在纯氮气环境中完整动物存活时间加倍，以及在长期给予丙戊酸盐后分离头部的呼吸活动（喘息）持续时间增加三倍，支持了这一推测。
