A SENSITIVE TECHNIQUE FOR THE DETECTION OF THE ALPHA-7 NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTOR ANTAGONIST, METHYLLYCACONITINE, IN RAT PLASMA AND BRAIN
A SENSITIVE TECHNIQUE FOR THE DETECTION OF THE ALPHA-7 NEURONAL NICOTINIC ACETYLCHOLINE-RECEPTOR ANTAGONIST, METHYLLYCACONITINE, IN RAT PLASMA AND BRAIN
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DOI：
10.1016/0165-0270(95)00032-p
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发表时间：
1995-09-01
影响因子：
3
通讯作者：
SULLIVAN, JP
中科院分区：
文献类型：
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作者：
TUREK, JW;KANG, CH;SULLIVAN, JP
Mmethyllycaconitine (MLA) 是 α-银环蛇毒素敏感的神经元烟碱乙酰胆碱受体 (nAChR) 的最有效和选择性拮抗剂。在本研究中，描述了一种从大鼠血浆和大脑中提取和分析 MLA 的准确且可重复的技术。这项研究进一步试图确定外周给药后大脑中是否可以达到药理学相关的 MLA 浓度。血浆样本的 MLA 检测限为 0.5 ng/ml，脑样本的 MLA 检测限为 1.0 ng/g。 MLA 在大鼠体内的药代动力学特性的特点是静脉内 (i.v.) 给药后消除半衰期短（19 分钟），而口服 (p.o.) 给药后生物利用度较差。值得注意的是，口服后消除半衰期显着延长。管理（408 分钟）。为了评估 MLA 渗入大脑的程度，在腹膜内 (i.p.) 给予未产生可观察到的副作用的一定剂量的 MLA 后，在不同时间点测定了 MLA 的大脑和血浆水平。最大血浆和脑水平分别为 694 +/- 106 ng/ml 和 32 +/- 3 ng/g。这些浓度在先前报道的范围内，可在体外选择性阻断 α7 nAChR 介导的反应。因此，外周给药的 MLA 可能是进一步探测体内 α7 nAChR 亚基的中枢神经系统功能的有用工具。
Methyllycaconitine (MLA) is the most potent and selective antagonist of the alpha-bungarotoxin sensitive neuronal nicotinic acetylcholine receptor (nAChR). In the present study, an accurate and reproducible technique for the extraction and analysis of MLA from rat plasma and brain is described. This study further sought to determine whether pharmacologically relevant concentrations of MLA could be achieved in brain following peripheral administration. The detection limits for MLA were 0.5 ng/ml for plasma samples and 1.0 ng/g for brain samples. The pharmacokinetic properties of MLA in rat are characterized by a short elimination half-life (19 min) following intravenous (i.v.) administration and poor bioavailability following oral (p.o.) administration. Remarkably, the elimination half-life is significantly longer following p.o. administration (408 min). To assess the extent to which MLA can penetrate into brain, brain and plasma levels of MLA were determined at different time points following intraperitoneal (i.p.) adminstration of a dose of MLA that produced no observable side effects. Maximal plasma and brain levels were 694 +/- 106 ng/ml and 32 +/- 3 ng/g, respectively. These concentrations are within a range previously reported to selectively block alpha 7 nAChR mediated responses in vitro. Peripherally administered MLA may therefore be a useful tool to further probe the central nervous system functions of the alpha 7 nAChR subunit in vivo.