Histamine protects against NMDA-induced necrosis in cultured cortical neurons through H2 receptor/cyclic AMP/protein kinase A and H3 receptor/GABA release pathways
Histamine protects against NMDA-induced necrosis in cultured cortical neurons through H2 receptor/cyclic AMP/protein kinase A and H3 receptor/GABA release pathways
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组胺通过 H2 受体/环磷酸腺苷/蛋白激酶 A 和 H3 受体/GABA 释放途径保护培养的皮质神经元免受 NMDA 诱导的坏死
DOI：
10.1111/j.1471-4159.2005.03633.x
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发表时间：
2006-03-01
影响因子：
4.7
通讯作者：
Chen, Z
中科院分区：
文献类型：
--
作者：
Dai, H;Zhang, Z;Chen, Z
使用组胺和 H-3 受体拮抗剂硫过酰胺，在大鼠培养的皮质神经元中研究了组胺受体在 NMDA 诱导的坏死中的作用。在强烈的 NMDA 损伤后 3 小时内，大多数神经元因坏死而死亡。组胺以浓度依赖性方式逆转神经毒性，并在浓度为10(-7) M时显示出最大保护作用。这种保护作用被H-2受体拮抗剂西咪替丁和唑兰替丁拮抗，但不被H-1受体拮抗剂吡拉明和苯海拉明拮抗。此外，选择性 H-2 受体激动剂氨胺模仿了组胺的保护作用。这种作用可以被西咪替丁阻止，但不能被吡拉明阻止。 8-Bromo-cAMP 也模仿组胺的作用。相比之下，腺苷酸环化酶抑制剂9-(四氢-2-呋喃基)-9H-嘌呤-6-胺和cAMP依赖性蛋白激酶抑制剂N-[2-(对溴肉桂氨基)乙基]-5-异喹啉磺酰胺均逆转了组胺的保护作用。 Thioperamide 还可减弱 NMDA 诱导的兴奋性毒性，这种毒性可被 H-3 受体激动剂 (R)-α-甲基组胺逆转，但不能被吡拉明和西咪替丁逆转。此外，GABA(A) 受体拮抗剂印防己毒素和荷包牡丹碱可抑制硫过酰胺的保护作用。进一步的研究表明，硫过酰胺的保护作用是由于 NMDA 刺激的样品中 GABA 释放增加所致。这些结果表明，不仅H-2受体/cAMP/cAMP依赖性蛋白激酶途径而且H-3受体/GABA释放途径都可以减弱NMDA诱导的神经毒性。
Using histamine and the H-3 receptor antagonist thioperamide, the roles of histamine receptors in NMDA-induced necrosis were investigated in rat cultured cortical neurons. Within 3 h of intense NMDA insult, most neurons died by necrosis. Histamine 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 H-2 receptor antagonists cimetidine and zolantidine but not by the H-1 receptor antagonists pyrilamine and diphenhydramine. In addition, the selective H-2 receptor agonist amthamine mimicked the protection by histamine. This action was prevented by cimetidine but not by pyrilamine. 8-Bromo-cAMP also mimicked the effect of histamine. In contrast, both the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine and the cAMP-dependent protein kinase inhibitor N-[2-(p-bromocinnamylamino) ethyl]-5-isoquinolinesulfonamide reversed the protection by histamine. Thioperamide also attenuated NMDA-induced excitotoxicity, which was reversed by the H-3 receptor agonist (R)-alpha-methylhistamine but not by pyrilamine and cimetidine. In addition, the protection by thioperamide was inhibited by the GABA(A) receptor antagonists picrotoxin and bicuculline. Further study demonstrated that the protection by thioperamide was due to increased GABA release in NMDA-stimulated samples. These results indicate that not only the H-2 receptor/cAMP/cAMP-dependent protein kinase pathway but also the H-3 receptor/GABA release pathway can attenuate NMDA-induced neurotoxicity.