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Sci Transl Med. 2018 May 30;10(443). pii: eaar3796. doi: 10.1126/scitranslmed.aar3796.

Pannexin-1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy.

Author information

1
Neuroglial Interactions in Cerebral Physiopathology, Center for Interdisciplinary Research in Biology, Collège de France, CNR UMR 7241, INSERM U1050, Labex Memolife, PSL Research University, 75005 Paris, France.
2
Assistance Publique-Hopitaux de Paris (AP-HP), Department of Pediatric Neurosurgery, Necker Hospital, INSERM U1129, Paris Descartes University, PRES Sorbonne Paris Cité, 75015 Paris, France.
3
INSERM U1129, Paris Descartes University, PRES Sorbonne Paris Cité, CEA, 75015 Paris, France.
4
CNRS UMR7355, Experimental and Molecular Immunology and Neurogenetics, 45067 Orléans, France.
5
Department of Neurosurgery, Sainte-Anne Hospital and IMA-BRAIN, INSERM U894, Paris Descartes University, PRES Sorbonne Paris Cité, 75014 Paris, France.
6
Department of Neurosurgery, University Pierre and Marie Curie, La Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Universités, 75013 Paris, France.
7
Department of Neurophysiology, La Pitié-Salpetrière Hospital, Sorbonne Universités, University Pierre and Marie Curie, AP-HP, 75013 Paris, France.
8
Neuroglial Interactions in Cerebral Physiopathology, Center for Interdisciplinary Research in Biology, Collège de France, CNR UMR 7241, INSERM U1050, Labex Memolife, PSL Research University, 75005 Paris, France. nathalie.rouach@college-de-france.fr.

Abstract

Epilepsies are characterized by recurrent seizures, which disrupt normal brain function. Alterations in neuronal excitability and excitation-inhibition balance have been shown to promote seizure generation, yet molecular determinants of such alterations remain to be identified. Pannexin channels are nonselective, large-pore channels mediating extracellular exchange of neuroactive molecules. Recent data suggest that these channels are activated under pathological conditions and regulate neuronal excitability. However, whether pannexin channels sustain or counteract chronic epilepsy in human patients remains unknown. We studied the impact of pannexin-1 channel activation in postoperative human tissue samples from patients with epilepsy displaying epileptic activity ex vivo. These samples were obtained from surgical resection of epileptogenic zones in patients suffering from lesional or drug-resistant epilepsy. We found that pannexin-1 channel activation promoted seizure generation and maintenance through adenosine triphosphate signaling via purinergic 2 receptors. Pharmacological inhibition of pannexin-1 channels with probenecid or mefloquine-two medications currently used for treating gout and malaria, respectively-blocked ictal discharges in human cortical brain tissue slices. Genetic deletion of pannexin-1 channels in mice had anticonvulsant effects when the mice were exposed to kainic acid, a model of temporal lobe epilepsy. Our data suggest a proepileptic role of pannexin-1 channels in chronic epilepsy in human patients and that pannexin-1 channel inhibition might represent an alternative therapeutic strategy for treating lesional and drug-resistant epilepsies.

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