Mapping Human Knowledge in Peripatetic Research: Mir., endoxa and the Limits of Beliefs
Date
2024
Authors
Baltussen, J.
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Abstracts of the International Conference: The Aristotelian Mirabilia, 2024, pp.1-1
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Han Baltussen
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International Conference: The Aristotelian Mirabilia (21 Apr 2022 - 23 Apr 2022 : Université Côte d’Azur, Nice, France)
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Abstract
OBJECTIVE: Hyperactive KCNT1 potassium channels, caused by gain-of-function mutations, are associated with a range of epilepsy disorders. Patients typically experience drug-resistant seizures and, in cases with infantile onset, developmental regression can follow. KCNT1-related disorders include epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. There are currently no effective treatments for KCNT1 epilepsies, but suppressing overactive channels poses a potential strategy. METHODS: Using the KCNT1 channel structure we in silico screened a library of known drugs for those predicted to block the channel pore to inhibit channel activity. Cellular KCNT1 channel inhibition was analyzed using electrophysiology and Drosophila bang-sensitive assays were used to analyze seizure suppression. Brain penetration of one drug was analyzed using liquid chromatography-mass spectrometry in a mouse. RESULTS: Eight known drugs were investigated in vitro for their effects on patient-specific mutant KCNT1 channels, with 4 drugs showing significant reduction of K+ current amplitudes. The action of the 4 drugs was then analyzed in vivo and 2 were found to reduce the seizure phenotype in humanized Drosophila KCNT1 epilepsy models. One drug, antrafenine, was shown to cross the blood-brain barrier in mice. INTERPRETATION: This study identified a known drug, antrafenine, that reduces KCNT1 channel activity, reduces seizure activity in Drosophila, and crosses the blood-brain barrier in the mouse, suggesting its potential applicability as a new treatment for KCNT1 epilepsy. The sequential in silico, in vitro, and in vivo mechanism-based drug selection strategy used here may have broader application for other human disorders where a disease mechanism has been identified. ANN NEUROL 2025.
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