Wang M, Li Y, Lin Y
Centre for Neuroscience, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou 215123, China; Department of Biological Sciences, XJTLU, Suzhou 215123, China.
Centre for Neuroscience, Xi'an Jiaotong-Liverpool University (XJTLU), Suzhou 215123, China.
Neuroscience. 2015 Jul 9;298:137-44. doi: 10.1016/j.neuroscience.2015.04.016. Epub 2015 Apr 18.
Cortical spreading depression (SD) is a transient propagating neuronal excitation followed by depression, which is generally accepted as the underlying cause of migraine. The inhibitory γ-aminobutyric acid type A (GABAA) receptor activation not only reduces cortical SD frequency and propagation, but also relieves migraine headache. This study aims to determine the role of major α subtypes of GABAA receptor in mediating SD genesis and propagation using an efficient in vitro chick retinal model. We firstly demonstrated that abundant α2, and to a lesser extent, α5 of GABAA receptor expression in the chick retina, enabled the tissue useful for studying GABAA receptor pharmacology and SD. Marked suppression of SD by SL651498 and TPA023 was observed at 10 μmol L(-1) and 50 μmol L(-1), respectively, suggesting a critical role of GABAA receptor α subtypes, in particular α2, in modulating retinal SD elicitation and propagation. The negative data on NS11394 at 3 μmol L(-1) on SD and the little positive selectivity of TPA023 for α5 did not support that α5 subtype is involved in SD genesis and propagation. Our data provide strong evidence that α2, but not α5 is involved in the early stage of migraine, indicating that α2 subtype is a possible drug target related to migraine with aura.
皮层扩散性抑制（SD）是一种短暂的、先有神经元兴奋随后出现抑制的传播过程，普遍被认为是偏头痛的潜在病因。抑制性γ-氨基丁酸A型（GABAA）受体激活不仅能降低皮层扩散性抑制的频率和传播速度，还能缓解偏头痛性头痛。本研究旨在利用高效的体外鸡视网膜模型，确定GABAA受体主要α亚型在介导皮层扩散性抑制的发生和传播中的作用。我们首先证明，鸡视网膜中GABAA受体α2大量表达，α5表达较少，这使得该组织可用于研究GABAA受体药理学和皮层扩散性抑制。分别在10 μmol L⁻¹和50 μmol L⁻¹时观察到SL651498和TPA023对皮层扩散性抑制有明显抑制作用，表明GABAA受体α亚型，特别是α2，在调节视网膜皮层扩散性抑制的诱发和传播中起关键作用。3 μmol L⁻¹的NS11394对皮层扩散性抑制无作用的数据以及TPA023对α5的微弱阳性选择性，不支持α5亚型参与皮层扩散性抑制的发生和传播。我们的数据提供了有力证据，表明α2而非α5参与偏头痛的早期阶段，这表明α2亚型可能是与先兆偏头痛相关的药物靶点。
