A novel approach for in vivo screening of toxins using the Drosophila Giant Fiber circuit.
A novel approach for in vivo screening of toxins using the Drosophila Giant Fiber circuit.
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DOI：
10.1016/j.toxicon.2010.08.005
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发表时间：
2010-12
期刊：
影响因子：
2.8
通讯作者：
Godenschwege, Tanja A.
中科院分区：
文献类型：
--
作者：
Mejia, Monica;Heghinian, Mari D.;Busch, Alexandra;Armishaw, Chris J.;Mari, Frank;Godenschwege, Tanja A.
关键词：
发现影响神经元或肌肉功能的化合物作为多种神经障碍的潜在治疗剂具有极大的兴趣。这些化合物的替代应用包括它们作为分子探针以及杀虫剂的用途。我们已经开发了一种生物测定，需要少量的化合物，并允许在体内的生物活性的无偏筛选。为此，我们以非侵入性的方式将化合物与来自特征良好的神经元回路的同时电生理记录配对，所述神经元回路是果蝇的巨纤维系统，其介导果蝇的逃避反应。该回路包括各种具有胆碱能、突触能和电突触以及神经肌肉接头的神经元。来自该系统的电生理记录允许检测针对这些组分上的任何分子靶标的化合物相关效应。在这里，我们提供的证据表明，这种新型生物测定法适用于胆碱能受体阻滞剂盐酸美加明和钾通道阻滞剂氢氧化四乙铵等小分子，以及棕色芋螺毒液和分离的锥形肽。锥肽已被开发成强效药物，如止痛药Prialt™和Xen 2174。然而，大多数锥肽尚未被表征，揭示了对快速和直接筛选方法的需要。我们的研究结果表明，美加明盐酸盐以及α-芋螺毒素ImI（已知是人类α7烟碱乙酰胆碱受体的拮抗剂）有效地破坏了果蝇α7烟碱乙酰胆碱受体依赖性通路的突触传递，但不影响具有其他类型突触的神经元的功能。这表明，我们的生物测定是一个有效的工具，用于筛选与人类健康相关的化合物。
Finding compounds that affect neuronal or muscular function is of great interest as potential therapeutic agents for a variety of neurological disorders. Alternative applications for these compounds include their use as molecular probes as well as insecticides. We have developed a bioassay that requires small amounts of compounds and allows for unbiased screening of biological activity in vivo. For this, we paired administering compounds in a non-invasive manner with simultaneous electrophysiological recordings from a well-characterized neuronal circuit, the Giant Fiber System of Drosophila melanogaster, which mediates the escape response of the fly. The circuit encompasses a variety of neurons with cholinergic, glutamatergic, and electrical synapses as well as neuromuscular junctions. Electrophysiological recordings from this system allow for the detection of compound-related effects against any molecular target on these components. Here, we provide evidence that this novel bioassay works with small molecules such as the cholinergic receptor blocker mecamylamine hydrochloride and the potassium channel blocker tetraethylammonium hydroxide, as well as with venom from Conus brunneus and isolated conopeptides. Conopeptides have been developed into powerful drugs, such as the painkillers Prialt™ and Xen2174. However, most conopeptides have yet to be characterized, revealing the need for a rapid and straightforward screening method. Our findings show that mecamylamine hydrochloride, as well as the α-conotoxin ImI, which is known to be an antagonist of the human α7 nicotinic acetylcholine receptor, efficiently disrupted the synaptic transmission of a Drosophila α7 nicotinic acetylcholine receptor-dependent pathway in our circuit but did not affect the function of neurons with other types of synapses. This demonstrates that our bioassay is a valid tool for screening for compounds relevant to human health.
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影响因子：
9.8
作者：
Fayyazuddin A;Zaheer MA;Hiesinger PR;Bellen HJ
通讯作者：
Bellen HJ
影响因子：
1.9
作者：
Godenschwege TA;Murphey RK
通讯作者：
Murphey RK
DOI：
10.1111/j.1460-9568.2007.05686.x
发表时间：
2007-07
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Allen MJ;Murphey RK
通讯作者：
Murphey RK
DOI：
10.1085/jgp.58.4.413
发表时间：
1971-10
期刊：
The Journal of general physiology
影响因子：
--
作者：
Armstrong CM
通讯作者：
Armstrong CM
影响因子：
3
作者：
Davis, Jasmine;Jones, Alun;Lewis, Richard J.
通讯作者：
Lewis, Richard J.