Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.
J Neurosci Res. 2017 Nov;95(11):2286-2296. doi: 10.1002/jnr.24057. Epub 2017 Apr 11.
A large body of evidence suggests that the neuropeptide galanin plays an important role in seizure control. In line with this, it was demonstrated that the galanin analogue, NAX-5055, exerts a potent anticonvulsant activity in animal seizure models. We recently found that the NAX-5055-mediated anticonvulsant action involves modulation of both excitatory and inhibitory neurotransmission. Since homeostasis of neurotransmitters and cerebral energy metabolism are intimately linked, it was investigated whether the effects of NAX-5055 on neurotransmission involve changes in energy metabolism and in particular glucose- and amino acid metabolism. With this aim, cultured neurons from mouse brain were incubated with [U- C]glucose in absence or presence of NAX-5055. Since effects of NAX-5055 on neurotransmission were detected during repetitive stimulation, we tested potential metabolic effects while mimicking repetitive bursts of neurotransmitter release as occurring in the intact brain. The metabolic pathways were mapped using gas-chromatography coupled to mass-spectrometry. We found that NAX-5055 does not modify glucose metabolism in glutamatergic and GABAergic neurons. Furthermore, the effect of NAX-5055 on astrocyte-neuron metabolic interactions was investigated by incubating co-cultures of astrocytes and either glutamatergic or GABAergic neurons with [U- C]glucose or the glial-selective substrate [1,2- C]acetate, with or without NAX-5055. In the presence of NAX-5055, no changes in the metabolic landscape were traced. The findings suggest that the anticonvulsant action of NAX-5055 and the accompanying changes in neurotransmission do not involve alterations in energy and amino acid metabolism. Hence, NAX-5055 appears to be an anti-seizure drug candidate displaying no unwanted side effects concerning brain energy and amino acid homeostasis. © 2017 Wiley Periodicals, Inc.
大量证据表明，神经肽甘丙肽在控制癫痫发作中起着重要作用。与此一致，研究表明甘丙肽类似物 NAX-5055 在动物癫痫发作模型中具有强大的抗惊厥作用。我们最近发现，NAX-5055 介导的抗惊厥作用涉及到兴奋性和抑制性神经递质传递的调节。由于神经递质和脑能量代谢的动态平衡密切相关，因此研究了 NAX-5055 对神经递质传递的影响是否涉及能量代谢的变化，特别是葡萄糖和氨基酸代谢的变化。为此，用 [U- C]葡萄糖孵育来自小鼠大脑的培养神经元，有无 NAX-5055 存在。由于在重复刺激期间检测到 NAX-5055 对神经传递的影响，因此我们在模拟完整大脑中发生的重复神经递质释放爆发的情况下测试了潜在的代谢效应。使用气相色谱法与质谱法相结合来绘制代谢途径。我们发现 NAX-5055 不会改变谷氨酸能和 GABA 能神经元中的葡萄糖代谢。此外，通过用 [U- C]葡萄糖或神经胶质选择性底物 [1,2- C]醋酸盐孵育星形胶质细胞和谷氨酸能或 GABA 能神经元的共培养物，研究了 NAX-5055 对星形胶质细胞-神经元代谢相互作用的影响，有无 NAX-5055 存在。在 NAX-5055 存在的情况下，没有追踪到代谢景观的变化。这些发现表明，NAX-5055 的抗惊厥作用和伴随的神经传递变化不涉及能量和氨基酸代谢的改变。因此，NAX-5055 似乎是一种抗癫痫候选药物，不会对大脑能量和氨基酸动态平衡产生不良的副作用。 © 2017 威利父子公司
