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Pathophysiology and treatments of brain ischemia insighted from neuronal function, metabolism and molecular structure

从神经元功能、代谢和分子结构洞察脑缺血的病理生理学和治疗

基本信息

批准号：
04304042
负责人：
SHIMOJI Koki
金额：
$ 8.96万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Co-operative Research (A)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-04304042/
关键词：
Brain ischemia Intracellular calcium Long term potentiation Calcium channel NMDA receptor Calcium binding protein cDNA subtraction Nitric oxide NMDAレセプタ NO アラキドン酸代謝系海馬スライス脳損傷海馬

项目摘要

(1)Increase in [Ca^<2+>] _i in response to oxygen-glucose deprivation was inhibited in mechanically injured hippocampal slices in comparison with non-injured slices 1-3 days after the injury. The fact suggests that intrinsic anti-ischemic activity may be induced in the vicinity of the injury. (2)Irreversible neuronal changes may be produced at 1-1.5 minfollowing a rapid depolarization of membrane potential induced by oxygen-glucose deprivation. Both Ca^<2+>-influx through NMDA receptor channels and Ca^<2+>release from intracellular site may associate the irreversible neuronal changes. (3) Mild acidosis inhibited both of increases in [Ca^<2+>] _i and membrane depolarization of hippocampal neurons in response to oxygen-glucose deprivation. (4)Active changes in [Ca^<2+>] _i in glial cells indicate important roles of glia for induction of LTP and ischemic changes in neurons.(5)LTP in hippocampal mossy fiber-CA3 synaps was suggested to be induced presynaptically. (6)Voltage-gated calcium channels contributing to release of chemical transmitters in hippocampus are assigned to be P-and L-type high threshold calcium channels but not to N-type calcium channels. (7)The molecular structure of subtypes composing the NMDA receptors was determined. Different distributions of each subtype may relate to vulnerability of neurons to ischemic damage. (8)Calcium binding proteins associating with neurotransmitter release from presynaptic membrane were determined. These proteins may associate with receptor-mediated intracellular signal transductions. (9)To assess unknown gene family induced by ischemia, new and high-sensitive cDNA subtraction method "directional tag PCR subtraction" was developed. (10)Nitric oxide synthase inhibitor reduced the infarction area. Inhibitors of the arachidonic acid metabolism inhibited the irreversible neuronal depolarization in hippocampal slices.

（1）机械损伤后1-3天海马脑片[Ca^<2+>] _i的增加受氧糖剥夺的抑制。这一事实表明，内在的抗缺血活性可能是在损伤附近诱导的。（2）缺氧缺糖引起的膜电位快速去极化后1- 1.5min可引起不可逆的神经元变化。NMDA受体通道的Ca^<2+>内流和胞内Ca^<2+>释放可能与神经元的不可逆变化有关。(3)轻度酸中毒可抑制缺氧缺糖引起的海马神经元[Ca^<2+>] i升高和膜去极化。（4）胶质细胞内[Ca^<2+>] i的活跃变化表明胶质细胞在诱导LTP和神经元缺血性改变中起重要作用。（5）海马苔藓纤维-CA_3突触LTP可能在突触前发生。（6）海马内参与化学递质释放的电压门控性钙通道属于P型和L型高阈值钙通道，而不是N型钙通道。（7）确定了NMDA受体亚型的分子结构。各亚型的不同分布可能与神经元对缺血性损伤的易感性有关。（8）测定突触前膜上与神经递质释放相关的钙结合蛋白。这些蛋白质可能与受体介导的细胞内信号转导有关。(9)To为评估缺血诱导的未知基因家族，建立了一种新的高灵敏度的cDNA消减方法“定向标签PCR消减法”。（10）一氧化氮合酶抑制剂可缩小梗死面积。花生四烯酸代谢抑制剂可抑制海马脑片不可逆的神经元去极化。