Effects of bilobalide, ginkgolide B and picrotoxinin on GABAA receptor modulation by structurally diverse positive modulators
Effects of bilobalide, ginkgolide B and picrotoxinin on GABAA receptor modulation by structurally diverse positive modulators
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DOI：
10.1016/j.ejphar.2017.04.019
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发表时间：
2017-07-05
影响因子：
5
通讯作者：
Johnston, Graham A. R.
中科院分区：
文献类型：
--
作者：
Ng, Chiu Chin;Duke, Rujee K.;Johnston, Graham A. R.
抗惊厥药和抗惊厥药通常正向调节GABA的作用，而许多惊厥药（包括氯离子通道阻断剂苦毒素）则负向调节GABA（A）受体上GAGA的作用。银杏内酯和银杏内酯B（银杏叶的活性成分）与苦毒素一样，已显示对GABA在α（1）β（2）γ（2L）GABA（A）受体上的作用有负调节作用。然而，与印防己毒素不同，银杏内酯和银杏内酯B并不知道会引起惊厥。我们已经评估了白果内酯、银杏内酯B和苦毒素对一系列GABA（A）调节剂（依托咪酯、洛瑞唑、丙泊酚、硫喷妥钠、地西泮和别孕烯醇酮）的作用，在爪蟾卵母细胞中表达的重组α（1）β（2）γ（2L）GABA（A）受体上使用双电极电压钳电生理学。结果表明，白果内酯和银杏内酯B与印防己毒素的不同之处在于它们抑制一系列这些结构不同的GABA（A）阳性调节剂的作用的能力，这与这些调节剂作用于与GABA（A）受体相关的多个活性位点一致。在GABA存在的情况下，银杏内酯B在抑制丙泊酚的GABA增强作用方面比白果内酯更有效，对洛瑞唑和别孕烯醇酮的作用等效，对依托咪酯、地西泮和硫喷妥钠的作用较弱。这表明与印防己毒素相比，白果内酯和银杏内酯B对不同调节剂的作用不同。
Anxiolytics and anticonvulsants generally positively modulate the action of GABA, whereas many convulsants (including the chloride channel blocker picrotoxinin) negatively modulate the action of GAGA on GABA(A) receptors. Like picrotoxinin, bilobalide and ginkgolide B, active constituents of Ginkgo biloba, have been shown to negatively modulate the action of GABA at alpha(1)beta(2)gamma(2L) GABA(A) receptors. However, unlike picrotoxinin, bilobalide and ginkgolide B are not known to cause convulsions. We have assessed the action of bilobalide, ginkgolide B and picrotoxinin on a range of GABA(A) modulators (etomidate, loreclezole, propofol, thiopentone sodium, diazepam, and allopregnanolone), using two-electrode voltage clamp electrophysiology at recombinant alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus oocytes. The results indicate that bilobalide and ginkgolide B differ from picrotoxinin in their ability to inhibit the actions of a range of these structurally diverse GABA(A) positive modulators consistent with these modulators acting on a multiplicity of active sites associated with GABA(A) receptors. In the presence GABA, ginkgolide B was more potent than bilobalide in inhibiting the GABA-potentiating effect of propofol, equipotent against loreclezole and allopregnanolone, and less potent against etomidate, diazepam, and thiopentone sodium. This indicates that in comparison to picrotoxinin, bilobalide and ginkgolide B differ in their effects on the different modulators.