| アブストラクト | Analysis platforms to predict drug-induced seizure liability at an early phase of drug development would improve safety and reduce attrition and the high cost of drug development. We hypothesized that a drug-induced in vitro transcriptomics signature predicts its ictogenicity. We exposed rat cortical neuronal cultures to non-toxic concentrations of 34 compounds for 24 h; 11 were known to be ictogenic (tool compounds), 13 were associated with a high number of seizure-related adverse event reports in the clinical FDA Adverse Event Reporting System (FAERS) database and systematic literature search (FAERS-positive compounds), and 10 were known to be non-ictogenic (FAERS-negative compounds). The drug-induced gene expression profile was assessed from RNA-sequencing data. Transcriptomics profiles induced by the tool, FAERS-positive and FAERS-negative compounds, were compared using bioinformatics and machine learning. Of the 13 FAERS-positive compounds, 11 induced significant differential gene expression; 10 of the 11 showed an overall high similarity to the profile of at least one tool compound, correctly predicting the ictogenicity. Alikeness-% based on the number of the same differentially expressed genes correctly categorized 85%, the Gene Set Enrichment Analysis score correctly categorized 73%, and the machine-learning approach correctly categorized 91% of the FAERS-positive compounds with reported seizure liability currently in clinical use. Our data suggest that the drug-induced gene expression profile could be used as a predictive biomarker for seizure liability. |
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| ジャーナル名 | International journal of molecular sciences |
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| Pubmed追加日 | 2023/2/26 |
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| 投稿者 | Lipponen, Anssi; Kajevu, Natallie; Natunen, Teemu; Ciszek, Robert; Puhakka, Noora; Hiltunen, Mikko; Pitkanen, Asla |
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| 組織名 | A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland,;P.O. Box 1627, FIN-70211 Kuopio, Finland.;Expert Microbiology Unit, Finnish Institute for Health and Welfare, P.O. Box 95,;FIN-70701 Kuopio, Finland.;Institute of Biomedicine, University of Eastern Finland, P.O. Box 1627, FIN-70211;Kuopio, Finland. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/36835526/ |
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