...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of applied toxicology >The NMDA receptor ion channel: a site for binding of Huperzine A.
【24h】

The NMDA receptor ion channel: a site for binding of Huperzine A.

机译：NMDA受体离子通道：石杉碱甲结合位点。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Huperzine A (HUP-A), first isolated from the Chinese club moss Huperzia serrata, is a potent, reversible and selective inhibitor of acetylcholinesterase (AChE) over butyrylcholinesterase (BChE) (Life Sci. 54: 991-997). Because HUP-A has been shown to penetrate the blood-brain barrier, is more stable than the carbamates used as pretreatments for organophosphate poisoning (OP) and the HUP-A:AChE complex has a longer half-life than other prophylactic sequestering agents, HUP-A has been proposed as a pretreatment drug for nerve agent toxicity by protecting AChE from irreversible OP-induced phosphonylation. More recently (NeuroReport 8: 963-968), pretreatment of embryonic neuronal cultures with HUP-A reduced glutamate-induced cell death and also decreased glutamate-induced calcium mobilization. These results suggest that HUP-A might interfere with and be beneficial for excitatory amino acid overstimulation, such as seen in ischemia, where persistent elevation of internal calcium levels by activation of the N-methyl-D-aspartate (NMDA) glutamate subtype receptor is found. We have now investigated the interaction of HUP-A with glutamate receptors. Freshly frozen cortex or synaptic plasma membranes were used, providing 60-90% specific radioligand binding. Huperzine A (< or =100 microM) had no effect on the binding of [3H]glutamate (low- and high-affinity glutamate sites), [3H]MDL 105,519 (NMDA glycine regulatory site), [3H]ifenprodil (NMDA polyamine site) or [3H]CGS 19755 (NMDA antagonist). In contrast with these results, HUP-A non-competitively (Hill slope < 1) inhibited [3H]MK-801 and [3H]TCP binding (co-located NMDA ion channel PCP site) with pseudo K(i) approximately 6 microM. Furthermore, when neuronal cultures were pretreated with HUP-A for 45 min prior to NMDA exposure, HUP-A dose-dependently inhibited the NMDA-induced toxicity. Although HUP-A has been implicated to interact with cholinergic receptors, it was without effect at 100 microM on muscarinic (measured by inhibition of [3H]QNB or [3H]NMS binding) or nicotinic [3H]epibatidine binding) receptors; also, HUP-A did not perturb adenosine receptor binding [3H]PIA or [3H]NECA). Therefore, HUP-A most likely attenuates excitatory amino acid toxicity by blocking the NMDA ion channel and subsequent Ca2+ mobilization at or near the PCP and MK-801 ligand sites. Thus, on the one hand, HUP-A could be used as a pretreatment against OPs and it might also be a valuable therapeutic intervention in a variety of acute and chronic disorders by protecting against overstimulation of the excitatory amino acid pathway. By blocking NMDA ion channels without psychotomimetic side-effects, HUP-A may protect against diverse neurodegenerative states observed during ischemia or Alzheimer's disease. Copyright 2001 John Wiley & Sons, Ltd.
机译：石杉甲A（HUP-A）首先从中国苔藓石杉（Huperzia serrata）分离，是一种有效，可逆和选择性的乙酰胆碱酯酶（AChE）抑制剂，优于丁酰胆碱酯酶（BChE）（生命科学54：991-997）。由于已证明HUP-A可以穿透血脑屏障，因此比用作有机磷中毒（OP）预处理的氨基甲酸酯更稳定，并且HUP-A：AChE复合物的半衰期比其他预防性隔离剂更长，通过保护AChE不受不可逆的OP诱导的磷酸化作用，HUP-A已被提议作为神经毒剂毒性的预处理药物。最近（NeuroReport 8：963-968），用HUP-A预处理胚胎神经元培养物减少了谷氨酸诱导的细胞死亡，也减少了谷氨酸诱导的钙动员。这些结果表明，HUP-A可能会干扰兴奋性氨基酸的过度刺激并对其有益，例如在局部缺血中，后者是通过激活N-甲基-D-天冬氨酸（NMDA）谷氨酸亚型受体而持续升高内部钙水平的。找到了。现在我们已经研究了HUP-A与谷氨酸受体的相互作用。使用新鲜冷冻的皮质或突触质膜，提供60-90％的特异性放射性配体结合。石杉碱甲（<或= 100 microM）对[3H]谷氨酸（低和高亲和力谷氨酸位点），[3H] MDL 105,519（NMDA甘氨酸调节位点），[3H] ifenprodil（NMDA多胺）的结合没有影响站点）或[3H] CGS 19755（NMDA拮抗剂）。与这些结果相反，HUP-A非竞争性地（希尔坡度<1）抑制了[3H] MK-801和[3H] TCP结合（位于同一位置的NMDA离子通道PCP位点），假K（i）约为6 microM 。此外，当在NMDA暴露之前用HUP-A对神经元培养物预处理45分钟时，HUP-A剂量依赖性地抑制NMDA诱导的毒性。尽管已经暗示HUP-A与胆碱能受体相互作用，但在100 microM时对毒蕈碱（通过抑制[3H] QNB或[3H] NMS结合来测量）或烟碱型[3H] epibatidine结合）没有作用;同样，HUP-A不会干扰腺苷受体的结合[3H] PIA或[3H] NECA。因此，HUP-A最有可能通过阻断NMDA离子通道和随后在PCP和MK-801配体位点或附近的Ca2 +动员来减弱兴奋性氨基酸毒性。因此，一方面，HUP-A可用作抗OP的预处理，并且通过防止兴奋性氨基酸途径的过度刺激，HUP-A还可作为多种急慢性疾病的有价值的治疗手段。通过阻断没有拟精神病药物副作用的NMDA离子通道，HUP-A可以预防缺血或阿尔茨海默氏病期间观察到的多种神经变性状态。版权所有2001 John Wiley＆Sons，Ltd.

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号