Kinase Inhibitors with Antiepileptic Properties Identified with a Novel in Vitro Screening Platform

• Published in: International journal of molecular sciences Vol. 20; no. 10; p. 2502
• Main Authors: Liu, Jing, Schenker, Madison, Ghiasvand, Shabnam, Berdichevsky, Yevgeny
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21-05-2019; MDPI
• Subjects: Animal models; Brain; Brain-derived neurotrophic factor; cFMS inhibitor; Chronic effects; Convulsions & seizures; Cyclin-dependent kinase 5; Cytoskeleton; Endocytosis; Epilepsy; epileptogenesis; Exocytosis; Inflammation; Inhibitors; kinase; Kinases; Load; organotypic; phenotypic screen; receptor tyrosine kinase; seizure; Seizures; Signal transduction; src family kinases; Synaptogenesis; TrkB; epilepsy; TrkB; kinase; seizure; src family kinases; epileptogenesis; phenotypic screen; cFMS inhibitor; receptor tyrosine kinase; organotypic
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20102502

Kinase signaling plays an important role in acquired epilepsy, but only a small percentage of the total kinome has been investigated in this context. A major roadblock that prevents the systematic investigation of the contributions of kinase signaling networks is the slow speed of experiments designed to test the chronic effects of target inhibition in epilepsy models. We developed a novel in vitro screening platform based on microwire recordings from an organotypic hippocampal culture model of acquired epilepsy. This platform enables the direct, parallel determination of the effects of compounds on spontaneous epileptiform activity. The platform also enables repeated recordings from the same culture over two-week long experiments. We screened 45 kinase inhibitors and quantified their effects on seizure duration, the frequency of paroxysmal activity, and electrographic load. We identified several inhibitors with previously unknown antiepileptic properties. We also used kinase inhibition profile cross-referencing to identify kinases that are inhibited by seizure-suppressing compounds, but not by compounds that had no effect on seizures.