Nuclear disintegration as a leading step of glutamate excitotoxicity in brain neurons
Nuclear disintegration as a leading step of glutamate excitotoxicity in brain neurons
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核崩解是脑神经元谷氨酸兴奋毒性的首要步骤
DOI：
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发表时间：
1996
影响因子：
4.2
通讯作者：
K. Hirakawa
中科院分区：
文献类型：
--
作者：
J. Ikeda;S. Terakawa;S. Murota;I. Morita;K. Hirakawa
最近的研究缺血性脑疾病在体内和谷氨酸兴奋毒性在体外表明，细胞凋亡可能发挥作用的兴奋毒性神经元死亡。为了研究谷氨酸兴奋性毒性中细胞凋亡的可能参与，我们研究了暴露于1 mM谷氨酸的大鼠皮层神经元的形态学变化的早期过程。在Nomarski光学系统下结合数字图像处理器进行的观察显示，细胞核发生快速变化，随后出现细胞肿胀。细胞核在5 min内颗粒增大并肿胀，然后在30 min内液化。细胞体在15-45 min内缓慢肿胀。这些变化可通过MK-801（马来酸地佐环平）（一种N-甲基-D-天冬氨酸（NMDA）受体偶联离子通道阻断剂）处理神经元来预防。然而，用一氧化氮合酶抑制剂NG-硝基-L-精氨酸（N-NORG）处理神经元没有显着影响。使用原位末端标记技术证明游离3′-羟基末端显示，DNA片段化发生在谷氨酸暴露后1小时内。在激光共聚焦显微镜下用fluo-3检查细胞内Ca 2+浓度的变化。应用1 mM谷氨酸诱导细胞核以及细胞质中的快速钙瞬变。这两种Ca反应均被MK-801阻断。这些结果表明，谷氨酸兴奋性毒性在脑神经元中不满足细胞凋亡的形态学标准，但表明，与DNA片段化相关的核解体参与谷氨酸兴奋性毒性的主导步骤。© 1996 Wiley利斯公司
Recent studies on ischemic brain disease in vivo and glutamate excitotoxicity in vitro suggest that apoptosis may play a role in excitotoxic neuronal death. To examine the possible involvement of apoptosis in glutamate excitotoxicity, we studied an early process of morphological changes in rat cortical neurons exposed to 1 mM glutamate. Observations under Nomarski optics combined with a digital image processor revealed a rapid change in the nucleus followed by a cellular swelling. The nucleus increased in granularity and swelled in 5 min, then became liquefied in 30 min. The cell body swelled slowly in 15–45 min. These changes could be prevented by treatment of the neuron with MK‐801 (dizocilpine maleate), a blocker of N‐methyl‐D‐aspartate (NMDA) receptor‐coupled ion channel. However, treatment of the neurons with NG‐nitro‐L‐arginine (N‐NORG), a nitric oxide synthase inhibitor, had no significant effect. Use of the in situ end‐labeling technique for the demonstration of free 3′‐hydroxyl ends revealed that DNA fragmentation took place within 1 hr after glutamate exposure. A change in intracellular Ca2+ concentration was examined with fluo‐3 under a confocal laser microscope. Application of 1 mM glutamate induced rapid Ca transients in the nucleus as well as in the cytoplasm. Both of these Ca responses were blocked by MK‐801. These results indicate that glutamate excitotoxicity in the brain neuron does not fulfill morphological criteria of apoptosis, but suggest that the nuclear disintegration associated with DNA fragmentation is involved as a leading step in glutamate excitotoxicity. © 1996 Wiley‐Liss, Inc.
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DOI：
10.1073/pnas.90.17.7951
发表时间：
1993-09-01
影响因子：
11.1
作者：
LOO, DT;COPANI, A;COTMAN, CW
通讯作者：
COTMAN, CW
发育性纹状体兴奋性毒性损伤后黑质的细胞凋亡。
DOI：
10.1073/pnas.91.17.8117
发表时间：
1994
影响因子：
11.1
作者：
Macaya,A;Munell,F;Gubits,RM;Burke,RE
通讯作者：
Burke,RE
DOI：
10.1073/pnas.88.14.6368
发表时间：
1991-07-01
影响因子：
11.1
作者：
DAWSON, VL;DAWSON, TM;SNYDER, SH
通讯作者：
SNYDER, SH
DOI：
10.1073/pnas.88.17.7797
发表时间：
1991-09-01
影响因子：
11.1
作者：
DAWSON, TM;BREDT, DS;SNYDER, SH
通讯作者：
SNYDER, SH