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Yen Neurological Foundation","award":["2013 research grant"],"award-info":[{"award-number":["2013 research grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2013PANX1 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\u2013PANX1 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\u2013PANX1 pore complex is a critical determinant of spreading depolarization susceptibility and its downstream consequences, of potential relevance to its signature disorders such as migraine.<\/jats:p>","DOI":"10.1093\/brain\/awx085","type":"journal-article","created":{"date-parts":[[2017,3,21]],"date-time":"2017-03-21T19:08:52Z","timestamp":1490123332000},"page":"1643-1656","source":"Crossref","is-referenced-by-count":121,"title":["Inhibition of the P2X7\u2013PANX1 complex suppresses spreading depolarization and neuroinflammation"],"prefix":"10.1093","volume":"140","author":[{"given":"Shih-Pin","family":"Chen","sequence":"first","affiliation":[{"name":"1 Neurovascular Research Lab, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA"},{"name":"2 Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan"},{"name":"3 Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Qin","sequence":"additional","affiliation":[{"name":"1 Neurovascular Research Lab, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Seidel","sequence":"additional","affiliation":[{"name":"1 Neurovascular Research Lab, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zheng","sequence":"additional","affiliation":[{"name":"1 Neurovascular Research Lab, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Eikermann","sequence":"additional","affiliation":[{"name":"4 Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA and Universitaet Duisburg Essen, Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel D.","family":"Ferrari","sequence":"additional","affiliation":[{"name":"5 Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arn M. J. M.","family":"van den Maagdenberg","sequence":"additional","affiliation":[{"name":"5 Department of Neurology, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands"},{"name":"6 Department of Human Genetics, Leiden University Medical Centre, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Moskowitz","sequence":"additional","affiliation":[{"name":"7 Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Charlestown, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cenk","family":"Ayata","sequence":"additional","affiliation":[{"name":"1 Neurovascular Research Lab, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA"},{"name":"8 Stroke Service and Neuroscience Intensive Care Unit, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 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