Inhibition of the P2X7-PANX1 complex suppresses spreading depolarization and neuroinflammation

Shih Pin Chen, Tao Qin, Jessica L. Seidel, Yi Zheng, Matthias Eikermann, Michel D. Ferrari, Arn M.J.M. Van Den Maagdenberg, Michael A. Moskowitz, Cenk Ayata, Katharina Eikermann-Haerter

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1643-1656
Number of pages14
JournalBrain
Volume140
Issue number6
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

Keywords

  • Migraine
  • Neuroinflammation
  • Purinergic receptor
  • Spreading depression
  • Trigeminovascular activation

ASJC Scopus subject areas

  • Clinical Neurology

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