HDT-1, a new synthetic compound, inhibits glutamate release in rat cerebral cortex nerve terminals （synaptosomes）  

作　　者：Su-jane WANG Shiu-huey CHOU Yuh-chi KUO Shang-shing Peter CHOU Woan-fang TZENG Jxh-yih LEU Rwei-fen S HUANG Yih-fong LIEW 

机构地区：[1]School of Medicine, Departments of Life Science Taipei Hsien, Taiwan 24205, China [2]School of Medicine, Departments of Chemistry Taipei Hsien, Taiwan 24205, China [3]School of Medicine, Departments of Nutritional Science, Fu Jen Catholic University, Taipei Hsien, Taiwan 24205, China

出　　处：《Acta Pharmacologica Sinica》2008年第11期1289-1295,共7页中国药理学报（英文版）

摘　　要：Aim： Excessive glutamate release has been proposed to be involved in the pathogenesis of several neurological diseases. In this study, we investigated the effect of HDT-1 （3, 4, 4a, 5, 8, 8a-hexahydro-6,7-dimethyl-4a-（phenylsulfonyl）- 2-tosylisoquinolin-1 （2H）-one）, a novel synthetic compound, on glutamate release in rat cerebrocortical nerve terminals and explored the possible mechanism. Methods： The release of glutamate was evoked by the K^＋ channel blocker 4-aminopyridine （4-AP） or the high external [K^＋] and measured by one-line enzyme-coupled fluorometric assay. We also determined the loci at which HDT-1 impinges on cerebrocortical nerve terminals by using membrane potentialsensitive dye to assay nerve terminal excitability and depolarization, and Ca^2＋ indicator Fura-2 to monitor Ca^2＋ influx. Results： HDT-1 inhibited the release of glutamate evoked by 4-AP and KCI in a concentration-dependent manner. HDT-1 did not alter the resting synaptosomal membrane potential or 4-APevoked depolarization. Examination of the effect of HDT-1 on cytosolic [Ca^2＋] revealed that the diminution of glutamate release could be attributed to reduction in voltage-dependent Ca^2＋ influx. Consistent with this, the HDT-1-mediated inhibition of glutamate release was significantly prevented in synaptosomes pretreated with the N- and P/Q-type Ca^2＋ channel blocker ω-conotoxin MVIIC. Conclusion： In rat cerebrocortical nerve terminals, HDT-1 inhibits glutamate release through a reduction of voltage-dependent Ca^2＋ channel activity and subsequent decrease of Ca^2＋ influx into nerve terminals, rather than any upstream effect on nerve terminal excitability.Aim： Excessive glutamate release has been proposed to be involved in the pathogenesis of several neurological diseases. In this study, we investigated the effect of HDT-1 （3, 4, 4a, 5, 8, 8a-hexahydro-6,7-dimethyl-4a-（phenylsulfonyl）- 2-tosylisoquinolin-1 （2H）-one）, a novel synthetic compound, on glutamate release in rat cerebrocortical nerve terminals and explored the possible mechanism. Methods： The release of glutamate was evoked by the K^＋ channel blocker 4-aminopyridine （4-AP） or the high external [K^＋] and measured by one-line enzyme-coupled fluorometric assay. We also determined the loci at which HDT-1 impinges on cerebrocortical nerve terminals by using membrane potentialsensitive dye to assay nerve terminal excitability and depolarization, and Ca^2＋ indicator Fura-2 to monitor Ca^2＋ influx. Results： HDT-1 inhibited the release of glutamate evoked by 4-AP and KCI in a concentration-dependent manner. HDT-1 did not alter the resting synaptosomal membrane potential or 4-APevoked depolarization. Examination of the effect of HDT-1 on cytosolic [Ca^2＋] revealed that the diminution of glutamate release could be attributed to reduction in voltage-dependent Ca^2＋ influx. Consistent with this, the HDT-1-mediated inhibition of glutamate release was significantly prevented in synaptosomes pretreated with the N- and P/Q-type Ca^2＋ channel blocker ω-conotoxin MVIIC. Conclusion： In rat cerebrocortical nerve terminals, HDT-1 inhibits glutamate release through a reduction of voltage-dependent Ca^2＋ channel activity and subsequent decrease of Ca^2＋ influx into nerve terminals, rather than any upstream effect on nerve terminal excitability.

关 键 词：isoquinoline alkaloid NEUROPROTECTION glutamate release voltage-dependent Ca^2＋ channel SYNAPTOSOME cerebral cortex 

分 类 号：R741[医药卫生—神经病学与精神病学]