Original Article

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

Authors: 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


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-l(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 fruorometric assay. We also determined the loci at which HDT-1 impinges on cerebrocortical nerve terminals by using membrane potential-sensitive dye to assay nerve terminal excitability and depolarization, and Ca2+ indicator Fura-2 to monitor Ca2+ influx.
Results: HDT-1 inhibited the release of glutamate evoked by 4-AP and KC1 in a concentration-dependent manner. HDT-1 did not alter the resting synaptosomal membrane potential or 4-AP-evoked depolarization. Examination of the effect of HDT-1 on cytosolic [Ca2+] revealed that the diminution of glutamate release could be attributed to reduction in voltage-dependent Ca2+ 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 Ca2+ channel blocker ω-conotoxin MVIIC.
Conclusion: In rat cerebrocortical nerve terminals, HDT-1 inhibits glutamate release through a reduction of voltage-dependent Ca2+ channel activity and subsequent decrease of Ca2+ influx into nerve terminals, rather than any upstream effect on nerve terminal excitability.

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