Olney J W, Ikonomidou C, Mosinger J L, Frierdich G
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110.
J Neurosci. 1989 May;9(5):1701-4. doi: 10.1523/JNEUROSCI.09-05-01701.1989.
Recent evidence implicates the endogenous excitatory amino acids, glutamate (Glu) and aspartate, in hypoxic/ischemic neuronal degeneration. In a preceding article (Ikonomidou et al., 1989) we described a new model for studying hypoxic/ischemic neuronal degeneration in the infant rat brain that entails unilateral common carotid artery ligation followed by exposure to a partial vacuum for 75 min. Promising features of this model include a low mortality rate and high incidence of acute brain damage disseminated over numerous brain regions. In addition, there is a striking similarity between the type of cytopathology characterizing this model of hypoxic/ischemic neuronal degeneration and that which has been described in infant animals treated with Glu. MK-801 is a powerful antagonist of the N-methyl-D-aspartate (NMDA) receptor ionophore complex (a subtype of Glu receptor). In the present study, after unilateral carotid artery ligation was performed on 10-d-old rat pups, they were treated either with MK-801 (1 mg/kg i.p.) or saline 15 min before exposure to the hypobaric condition. MK-801 exerted a strong neuroprotective effect without serious side effects; the majority of saline control animals sustained severe brain damage, whereas the majority of MK-801-treated pups had no brain damage. These and other recent findings suggest that the NMDA receptor may play an important role in hypoxic/ischemic neuronal degeneration in the immature brain and provide hope that NMDA antagonists such as MK-801 may be effective in preventing such degeneration.
最近有证据表明，内源性兴奋性氨基酸，即谷氨酸（Glu）和天冬氨酸，与缺氧/缺血性神经元变性有关。在前一篇文章（伊科诺米杜等人，1989年）中，我们描述了一种研究幼鼠脑缺氧/缺血性神经元变性的新模型，该模型包括单侧颈总动脉结扎，然后暴露于部分真空环境75分钟。该模型的显著特点包括死亡率低以及急性脑损伤在多个脑区广泛分布的高发生率。此外，表征这种缺氧/缺血性神经元变性模型的细胞病理学类型与用Glu处理的幼小动物中所描述的细胞病理学类型之间存在惊人的相似性。MK-801是N-甲基-D-天冬氨酸（NMDA）受体离子通道复合物（Glu受体的一种亚型）的强效拮抗剂。在本研究中，对10日龄的幼鼠进行单侧颈动脉结扎后，在暴露于低压环境前15分钟，分别用MK-801（1毫克/千克腹腔注射）或生理盐水处理。MK-801发挥了强大的神经保护作用且无严重副作用；大多数生理盐水对照动物遭受了严重的脑损伤，而大多数接受MK-801处理的幼鼠没有脑损伤。这些以及其他近期的研究结果表明，NMDA受体可能在未成熟脑的缺氧/缺血性神经元变性中起重要作用，并为诸如MK-801之类的NMDA拮抗剂可能有效预防这种变性带来了希望。
