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

作者：Elena Dossi, Thomas Blauwblomme, Julien Moulard, Oana Chever, Flora Vasile, Eléonore Guinard, Marc Le Bert, Isabelle Couillin, Johan Pallud, Laurent Capelle, Gilles Huberfeld, Nathalie Rouach · 发表于：Science Translational Medicine · 年份：2018 · DOI：10.1126/scitranslmed.aar3796 · 被引用次数：129 · 研究领域：Connexins and lens biology、Biochemical effects in animals、Neuroscience and Neuropharmacology Research

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-...