Spampanato Jay, Gibson Anne, Dudek F Edward
Department of Neurosurgery, University of Utah School of Medicine , Salt Lake City, Utah.
J Neurophysiol. 2018 May 1;119(5):1693-1698. doi: 10.1152/jn.00587.2017. Epub 2018 Jan 24.
Macrocyclic lactones (MLs) are commonly used treatments for parasitic worm and insect infections in humans, livestock, and companion animals. MLs target the invertebrate glutamate-activated chloride channel that is not present in vertebrates. MLs are not entirely inert in vertebrates, though; they have been reported to have activity in heterologous expression systems consisting of ligand-gated ion channels that are present in the mammalian central nervous system (CNS). However, these compounds are typically not able to reach significant concentrations in the CNS because of the activity of the blood-brain barrier P-glycoprotein extrusion system. Despite this, these compounds are able to reach low levels in the CNS that may be useful in the design of novel "designer" ligand-receptor systems that can be used to directly investigate neuronal control of behavior in mammals and have potential for use in treating human neurological diseases. To determine whether MLs might affect neurons in intact brains, we investigated the activity of the ML moxidectin (MOX) at native GABA receptors. Specifically, we recorded tonic and phasic miniature inhibitory postsynaptic currents (mIPSCs) in ex vivo brain slices. Our data show that MOX potentiated tonic GABA currents in a dose-dependent manner but had no concomitant effects on phasic GABA currents (i.e., MOX had no effect on the amplitude, frequency, or decay kinetics of mIPSCs). These studies indicate that behavioral experiments that implement a ML-based novel ligand-receptor system should take care to control for potential effects of the ML on native tonic GABA receptors. NEW & NOTEWORTHY We have identified a novel mechanism of action in the mammalian central nervous system for the antihelminthic moxidectin, commonly prescribed to animals worldwide and currently being evaluated for use in humans. Specifically, moxidectin applied to rodent brain slices selectively enhanced the tonic GABA conductance of hippocampal pyramidal neurons.
大环内酯类药物（MLs）是治疗人类、家畜和伴侣动物寄生虫和昆虫感染的常用药物。MLs作用于脊椎动物中不存在的无脊椎动物谷氨酸激活氯离子通道。然而，MLs在脊椎动物中并非完全无活性；据报道，它们在由哺乳动物中枢神经系统（CNS）中存在的配体门控离子通道组成的异源表达系统中具有活性。然而，由于血脑屏障P-糖蛋白外排系统的作用，这些化合物通常无法在中枢神经系统中达到显著浓度。尽管如此，这些化合物能够在中枢神经系统中达到低水平，这可能有助于设计新型的“设计型”配体-受体系统，可用于直接研究哺乳动物行为的神经元控制，并有可能用于治疗人类神经系统疾病。为了确定MLs是否会影响完整大脑中的神经元，我们研究了ML莫西菌素（MOX）在天然GABA受体上的活性。具体而言，我们在离体脑片中记录了强直和相位性微小抑制性突触后电流（mIPSCs）。我们的数据表明，MOX以剂量依赖性方式增强了强直GABA电流，但对相位性GABA电流没有伴随影响（即，MOX对mIPSCs的幅度、频率或衰减动力学没有影响）。这些研究表明，实施基于ML的新型配体-受体系统的行为实验应注意控制ML对天然强直GABA受体的潜在影响。新发现与值得注意的是我们已经在哺乳动物中枢神经系统中确定了抗蠕虫药莫西菌素的一种新作用机制，该药在全球范围内普遍用于动物，目前正在评估其在人类中的应用。具体而言，应用于啮齿动物脑片的莫西菌素选择性地增强了海马锥体神经元的强直GABA电导。
