Inhibition of release of taurine and excitatory amino acids in ischemia and neuroprotection
Inhibition of release of taurine and excitatory amino acids in ischemia and neuroprotection
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DOI：
10.1023/b:nere.0000010455.78121.53
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发表时间：
2004-01-01
影响因子：
4.4
通讯作者：
Feustel, PJ
中科院分区：
文献类型：
--
作者：
Kimelberg, HK;Nestor, NB;Feustel, PJ
体积调节阴离子通道（VRAC）已经在纯化的单细胞系统如细胞培养物中被广泛研究，其中它们可以通过细胞肿胀被激活。这提供了一种分析机制的方便方式，并且可能导致该领域的圣杯，即体积传感器的性质和VRAC的性质。这种理解的重要原因是，这些通道是普遍存在的，并具有重要的生理功能，在病理条件下转化为有害的影响。在这里，我们总结的数据显示，在缺血诱导的释放兴奋性氨基酸（EAA）的大鼠模型中的VRAC的参与。使用微透析研究，我们发现星形胶质细胞谷氨酸转运蛋白和VRAC的逆转对EAA的大量初始释放的贡献大致相等，并且共同占总释放的约80%。我们使用了非常有效的VRAC阻断剂他莫昔芬，以观察通过VRAC抑制EAA释放是否会导致显著的神经保护作用。在局灶性大鼠MCA闭塞模型中的治疗导致梗死面积减少约80%，有效的缺血治疗窗开始后为3小时。然而，即使是最有效的抑制剂也存在其他作用的共同问题，因为他莫昔芬具有其他潜在的神经保护作用。因此，其抑制硝基酪氨酸形成，可能是由于其抑制nNOS和减少过氧亚硝酸盐形成。虽然他莫昔芬不能因此被用作“VRAC-兴奋毒性”假设的测试，但由于其多靶点，它可能被证明成功地将基础中风研究转化为临床。
Volume regulated anion channels (VRAC) have been extensively studied in purified single cell systems like cell cultures where they can be activated by cell swelling. This provides a convenient way of analyzing mechanisms and will likely lead to the holy grails of the field, namely the nature or natures of the volume sensor and the nature or natures of VRACs. Important reasons for such an understanding are that these channels are ubiquitous and have important physiological functions which under pathological conditions convert to deleterious effects. Here we summarize data showing the involvement of VRACs in ischemia-induced release of excitatory amno acids (EAAs) in a rat model of global ischemia. Using microdialysis studies we found that reversal of the astrocytic glutamate transporter and VRACs contribute about equally to the large initial release of EAAs and together account for around 80% of the total release. We used the very potent VRAC blocker, tamoxifen, to see if such inhibition of EAA release via VRACs led to significant neuroprotection. Treatment in the focal rat MCA occlusion model led to around 80% reduction in infarct size with an effective post initiation of ischemia therapeutic window of three hours. However, the common problem of other effects for even the most potent inhibitors pertains here, as tamoxifen has other, potentially neuroprotective, effects. Thus it inhibits nitrotyrosine formation, likely due to its inhibition of nNOS and reduction of peroxynitrite formation. Although tamoxifen cannot therefore be used as a test of the "VRAC-excitotxicity" hypothesis it may prove successful for translation of basic stroke research to the clinic because of its multiple targets.