Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome

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(Griffin, et. al 2017). Building on previous drug screening in a Dravet syndrome model of zebrafish that identified clemizole, a histamine (H1) receptor antagonist, as having anti-epileptic properties, this study sought to further examine the mechanisms of clemizole\’s action and expand the class of serotonin-acting compounds to include, among others, the FDA-approved drugs lorcaserin (Belviq) and trazodone, and describes the treatment of five human patients with Dravet syndrome with lorcaserin in a small clinical study.

The 2013 finding that clemizole had potential to treat scn1Lab mutant zebrafish was surprising because antihistamines are traditionally contraindicated in pediatric epilepsy. Further study found that clemizole, but not other antihistamines, exerts antiepileptic activity in zebrafish models, and that it had a high affinity for histamine (H1) and serotonin (5-HT) receptors. This led the investigators to test other compounds known to have similar properties. The compounds were first tested to see if they reduced average swim velocity (locomotion), and whether or not they were toxic to the fish. Those that passed the locomotion test went on to electrographic (EEG-like) testing, where trazodone and lorcaserin continued to perform well. No manufacturer currently makes a clinical grade formulation of clemizole, and trazodone can act as either a serotonin receptor agonist or antagonist depending on concentration, so lorcaserin was chosen for human study.

Five patients were treated with lorcaserin (Belviq) at Children’s Hospital Colorado: All experienced a (varied) reduction in total seizures with decreased appetite as the most common side effect. This article describes the first progression from zebrafish drug screening to clinical study, and supports the increasing evidence that serotonin modulation (via fenfluramine or other agents) can be an effective treatment for epilepsies like Dravet syndrome.

Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC. Clemizole and modulators of serotonin signalling suppress seizures in Dravet syndrome. Brain. 2017 Jan 10. pii: aww342. doi: 10.1093/brain/aww342. [Epub ahead of print] PubMed PMID: 28073790.
Woman researcher using microscope in lab

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