Okuda Hiroaki, Ogita Kiyokazu
Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, 45-1, Nagaotoge-cho, Hirakata, 573-0101 Japan.
Nihon Shinkei Seishin Yakurigaku Zasshi. 2002 Oct;22(5):153-8.
Glutamate, the endogenous excitatory amino acid, is involved in the pathophysiology of the phenomenon of excitotoxic neuronal damages. Among glutamate receptors, NMDA receptors play a major role in these processes. In cultured cerebellar granule neurons, paradoxically, treatment with a subtoxic concentration of NMDA protects all of the vulnerable neurons present in the culture from an excitotoxic glutamate concentration. Neuroprotection by NMDA is mediated by a de novo synthesis of proteins such as brain-derived neurotrophic factor, whose expression is activated by the transcription factor NF kappa B. Therefore NF kappa B plays a critical role in NMDA-mediated neuroprotection against glutamate-induced damage in the cultured cerebellar granule neurons. Besides in vitro experiments, in vivo experiments with mice have been carried out to evaluate NMDA-mediated neuroprotective effects. A systemic administration of NMDA alone fails to cause neuronal cell death in any region of the hippocampus. Although an administration of kainate alone induces severe damage in pyramidal cells of the hippocampus, kainate-induced neuronal damages in the hippocampus are absolutely protected by a prior administration of NMDA. Taken together, NMDA receptors play the roles of both "accelerator" and "brake" in glutamate-induced neuronal damage.
谷氨酸作为内源性兴奋性氨基酸，参与了兴奋性毒性神经元损伤现象的病理生理过程。在谷氨酸受体中，N-甲基-D-天冬氨酸（NMDA）受体在这些过程中起主要作用。然而，在培养的小脑颗粒神经元中，用亚毒性浓度的NMDA处理可保护培养物中所有易损神经元免受兴奋性毒性谷氨酸浓度的损伤。NMDA的神经保护作用是由诸如脑源性神经营养因子等蛋白质的从头合成介导的，其表达由转录因子核因子κB（NF-κB）激活。因此，NF-κB在NMDA介导的对培养的小脑颗粒神经元中谷氨酸诱导损伤的神经保护作用中起关键作用。除了体外实验，还进行了小鼠体内实验以评估NMDA介导的神经保护作用。单独全身给予NMDA不会在海马体的任何区域导致神经元细胞死亡。虽然单独给予海藻酸会诱导海马体锥体细胞严重损伤，但预先给予NMDA可完全保护海藻酸诱导的海马体神经元损伤。综上所述，NMDA受体在谷氨酸诱导的神经元损伤中既起“加速器”又起“刹车”的作用。
