The histamine H3 receptor antagonist clobenpropit enhances GABA release to protect against NMDA-induced excitotoxicity through the cAMP/protein kinase A pathway in cultured cortical neurons
The histamine H3 receptor antagonist clobenpropit enhances GABA release to protect against NMDA-induced excitotoxicity through the cAMP/protein kinase A pathway in cultured cortical neurons
复制标题
组胺 H3 受体拮抗剂 clobenpropit 可增强 GABA 释放，从而通过 cAMP/蛋白激酶 A 途径在培养的皮层神经元中防止 NMDA 诱导的兴奋性毒性。
DOI：
10.1016/j.ejphar.2007.01.069
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发表时间：
2007-06-01
影响因子：
5
通讯作者：
Chen, Zhong
中科院分区：
文献类型：
--
作者：
Dai, Haibin;Fu, Qiuli;Chen, Zhong
用组胺H-3受体拮抗剂Clobenpropit研究了组胺H-3受体在NMDA诱导的大鼠皮层神经元坏死中的作用。Clobenpropit以浓度依赖性方式逆转神经毒性，并在10（-7）M浓度下显示出峰值保护作用。这种保护作用可被组胺H-3受体激动剂（R）-α-甲基组胺拮抗，但不能被组胺H-1受体拮抗剂吡拉明或组胺H-2受体拮抗剂西咪替丁拮抗。此外，GABA（A）受体拮抗剂印防己毒素和荷包牡丹碱可抑制clobenpropit的保护作用。进一步的研究表明，clobenpropit的保护作用是由于增加GABA的释放。诱导型GABA释放也被（R）-α-甲基组胺抑制，但不是由吡拉明或西咪替丁。此外，腺苷酸环化酶抑制剂SQ-22536和蛋白激酶A（PKA）抑制剂H-89都逆转了clobenpropit的保护作用和GABA的释放。此外，clobenpropit逆转NMDA诱导的细胞内钙水平的增加，这是由（R）-α-甲基双胺拮抗。这些结果表明，clobenpropit增强GABA的释放，以保护免受NMDA诱导的兴奋性毒性，这是通过cAMP/PKA途径诱导，细胞内钙水平的降低也可能参与。(c)2007 Elsevier B.V保留所有权利。
Using the histamine H-3 receptor antagonist clobenpropit, the roles of histamine H-3 receptors in NMDA-induced necrosis were investigated in rat cultured cortical neurons. Clobenpropit reversed the neurotoxicity in a concentration-dependent manner, and showed peak protection at a concentration of 10(-7) M. This protection was antagonized by the histamine H-3 receptor agonist (R)-alpha-methylhistamine, but not by the histamine H-1 receptor antagonist pyrilamine or the histamine H-2 receptor antagonist cimetidine. In addition, the protection by clobenpropit was inhibited by the GABA(A) receptor antagonists picrotoxin and bicuculline. Further study demonstrated that the protection by clobenpropit was due to increased GABA release. The inducible GABA release was also inhibited by (R)-alpha-methylhistamine, but not by pyrilamine or cimetidine. Furthermore, both the adenylyl cyclase inhibitor SQ-22536 and the protein kinase A (PKA) inhibitor H-89 reversed the protection and the GABA release by clobenpropit. In addition, clobenpropit reversed the NMDA-induced increase in intracellular calcium level, which was antagonized by (R)-alpha-methylbistamine. These results indicate that clobenpropit enhanced GABA release to protect against NMDA-induced excitotoxicity, which was induced through the cAMP/PKA pathway, and reduction of intracellular calcium level may also be involved. (c) 2007 Elsevier B.V All rights reserved.