Abstract
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.
Highlights
Characteristics of the epileptic brain include axon sprouting, synaptic reorganization, inflammation, and hyperexcitability [1,2]
Seizure durations per 1 h of recording, four vehicle-treated generated from same animal. for Seizure durations and per 1compared h of recording, average event rates,cultures and electrographic loadsthe were combined all recordings using average event rates, and electrographic loads were combined for all recordings and compared using a Kolmogorov–Smirnov test
The Pearson correlation coefficient was R2 = 0.369 with p < 0.001 for cumulative seizure time versus electrographic load, and R2 = 0.752 with p < 0.001 for cumulative seizure time versus average event rate. These results indicate that while the three metrics used to evaluate the results of the screen are not not completely completely independent independent of of one one another, another, cumulative cumulative seizure seizure time time and and electrographic electrographic load load are are only only weakly correlated
Summary
Characteristics of the epileptic brain include axon sprouting, synaptic reorganization, inflammation, and hyperexcitability [1,2]. Axon and dendritic growth and development, synaptic formation and maintenance, changes in receptor number and composition, and inflammatory processes are regulated by cell signaling pathway networks [2,3,4,5,6,7,8,9]. The inhibition of these pathways has the potential to prevent the formation of epileptic circuitry and prevent epilepsy development after brain injury, or even disrupt existing epileptic circuits and have a permanent disease-modifying effect.
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