Chen Shih-Pin, Qin Tao, Seidel Jessica L, Zheng Yi, Eikermann Matthias, Ferrari Michel D, van den Maagdenberg Arn M J M, Moskowitz Michael A, Ayata Cenk, Eikermann-Haerter Katharina
Neurovascular Research Lab, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.
Brain. 2017 Jun 1;140(6):1643-1656. doi: 10.1093/brain/awx085.
Spreading depolarization is a wave of neuronal and glial depolarization. Within minutes after spreading depolarization, the neuronal hemichannel pannexin 1 (PANX1) opens and forms a pore complex with the ligand-gated cation channel P2X7, allowing the release of excitatory neurotransmitters to sustain spreading depolarization and activate neuroinflammation. Here, we explore the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility with important consequences for neuroinflammation and trigeminovascular activation. We found that genetic loss of function or ablation of the P2x7 gene inhibits spreading depolarization. Moreover, pharmacological suppression of the P2X7-PANX1 pore complex inhibits spreading depolarization in mice carrying the human familial hemiplegic migraine type 1 R192Q missense mutation as well as in wild-type mice and rats. Pore inhibitors elevate the electrical threshold for spreading depolarization, and reduce spreading depolarization frequency and amplitude. Pore inhibitors also suppress downstream consequences of spreading depolarization such as upregulation of interleukin-1 beta, inducible nitric oxide synthase and cyclooxygenase-2 in the cortex after spreading depolarization. In addition, they inhibit surrogates for trigeminovascular activation, including expression of calcitonin gene-related peptide in the trigeminal ganglion and c-Fos in the trigeminal nucleus caudalis. Our results are consistent with the hypothesis that the P2X7-PANX1 pore complex is a critical determinant of spreading depolarization susceptibility and its downstream consequences, of potential relevance to its signature disorders such as migraine.
扩散性去极化是神经元和神经胶质去极化的一种波。在扩散性去极化发生后的几分钟内，神经元半通道泛素连接蛋白1（PANX1）打开，并与配体门控阳离子通道P2X7形成孔复合体，使兴奋性神经递质得以释放，以维持扩散性去极化并激活神经炎症。在此，我们探讨这样一种假说，即P2X7 - PANX1孔复合体是扩散性去极化易感性的关键决定因素，对神经炎症和三叉神经血管激活具有重要影响。我们发现，P2x7基因的功能丧失或缺失会抑制扩散性去极化。此外，对P2X7 - PANX1孔复合体的药理学抑制可抑制携带人类家族性偏瘫型偏头痛1型R192Q错义突变的小鼠以及野生型小鼠和大鼠的扩散性去极化。孔抑制剂提高了扩散性去极化的电阈值，并降低了扩散性去极化的频率和幅度。孔抑制剂还抑制了扩散性去极化的下游后果，例如扩散性去极化后皮质中白细胞介素 - 1β、诱导型一氧化氮合酶和环氧化酶 - 2的上调。此外，它们抑制三叉神经血管激活的替代指标，包括三叉神经节中降钙素基因相关肽的表达以及三叉神经尾核中c - Fos的表达。我们的结果与以下假说一致，即P2X7 - PANX1孔复合体是扩散性去极化易感性及其下游后果的关键决定因素，这可能与其标志性疾病如偏头痛相关。
