Research ArticleEpilepsy

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

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Science Translational Medicine  30 May 2018:
Vol. 10, Issue 443, eaar3796
DOI: 10.1126/scitranslmed.aar3796

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Repurposing drugs for epilepsy

Epilepsy is a neurological disorder characterized by seizures that impair day-to-day living and cause cognitive impairments. About 40% of patients with epilepsy do not respond to antiepileptic drugs, highlighting the need to identify new therapeutic targets for drug development. Dossi et al. used brain tissue samples from patients with epilepsy undergoing surgical resection and a mouse model of epilepsy to show that the membrane channel pannexin-1 contributes to seizure activity. Two approved drugs that block the pannexin-1 channel reduced epileptic activity in human brain tissue slices ex vivo and in a mouse model of the disease. The results suggest that the pannexin-1 channel might be a valid therapeutic target for developing drugs to treat pharmacoresistant epilepsy.

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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