Bernabeu R, Sharp F R
Department of Neurology, University of California, San Francisco, USA.
J Cereb Blood Flow Metab. 2000 Dec;20(12):1669-80. doi: 10.1097/00004647-200012000-00006.
The effect of N-methyl-D-aspartate (NMDA) and 2-(aminomethyl)phenylacetic acid/kainate (AMPA/kainate) glutamate receptors on dentate cell proliferation and hippocampal synapsin-I induction was examined after global ischemia. Cell proliferation was assessed using BrdU labeling, and synaptic responses were assessed using synapsin-I expression. Systemic glutamate receptor antagonists (MK-801 and NBQX) increased BrdU-labeled cells in the dentate subgranular zone (SGZ) of control adult gerbils (30% to 90%, P < 0.05). After global ischemia (at 15 days after 10 minutes of ischemia), most CA1 pyramidal neurons died, whereas the numbers of BrdU-labeled cells in the SGZ increased dramatically (>1000%, P < 0.0001). Systemic injections of MK801 or NBQX, as well as intrahippocampal injections of either drug, when given at the time of ischemia completely blocked the birth of cells in the SGZ and the death of CA1 pyramidal neurons at 15 days after ischemia. Glutamate receptor antagonists had little effect on cell birth and death when administered 7 days after ischemia. The induction of synapsin-I protein in stratum moleculare of CA3 at 7 and 15 days after global ischemia was blocked by pretreatment with systemic or intrahippocampal MK-801 or NBQX. It is proposed that decreased dentate glutamate receptor activation--produced by glutamate receptor antagonists in normal animals and by chronic ischemic hippocampal injury--may trigger dentate neurogenesis and synaptogenesis. The synapsin-I induction in mossy fiber terminals most likely represents re-modeling of dentate granule cell neuron presynaptic elements in CA3 in response to the ischemia. The dentate neurogenesis and synaptogenesis that occur after ischemia may contribute to memory recovery after hippocampal injury caused by global ischemia.
在全脑缺血后，研究了N-甲基-D-天冬氨酸（NMDA）和2-（氨甲基）苯乙酸/红藻氨酸（AMPA/红藻氨酸）谷氨酸受体对齿状细胞增殖和海马突触素-I诱导的影响。使用溴脱氧尿苷（BrdU）标记评估细胞增殖，使用突触素-I表达评估突触反应。全身性谷氨酸受体拮抗剂（MK-801和NBQX）可增加对照成年沙鼠齿状颗粒下层（SGZ）中BrdU标记的细胞（增加30%至90%，P<0.05）。全脑缺血后（缺血10分钟后15天），大多数CA1锥体神经元死亡，而SGZ中BrdU标记的细胞数量急剧增加（>1000%，P<0.0001）。在缺血时全身性注射MK801或NBQX，以及海马内注射这两种药物中的任何一种，均可在缺血后15天完全阻断SGZ中细胞的产生和CA1锥体神经元的死亡。谷氨酸受体拮抗剂在缺血7天后给药时，对细胞产生和死亡几乎没有影响。全身性或海马内注射MK-801或NBQX预处理可阻断全脑缺血后7天和15天CA3分子层中突触素-I蛋白的诱导。有人提出，正常动物中谷氨酸受体拮抗剂以及慢性缺血性海马损伤导致的齿状谷氨酸受体激活减少，可能会触发齿状神经发生和突触形成。苔藓纤维终末中突触素-I的诱导很可能代表CA3中齿状颗粒细胞神经元突触前元件对缺血的重塑。缺血后发生的齿状神经发生和突触形成可能有助于全脑缺血所致海马损伤后的记忆恢复。
