Can We Panelize Seizure?. (9th November 2020)

• Record Type: Journal Article
• Authors: Roberts, Ruth; Authier, Simon; Mellon, R Daniel; Morton, Michael; Suzuki, Ikuro; Tjalkens, Ronald B; Valentin, Jean-Pierre; Pierson, Jennifer B
• Is Part Of: Toxicological sciences. Volume 179:Number 1(2021)
• Page Start: 3
• Page End: 13
• Publication Date: 2020-11-09
• Subjects: CNS -- ion channels -- MEA -- seizure -- neurotoxicology -- drug development -- in vitro models -- induced pluripotent stem cells -- neuron -- regulatory sciences; Toxicology -- Periodicals; Toxicology -- Periodicals; Toxicology; Periodicals; 615.9
• DOI: 10.1093/toxsci/kfaa167
• Languages: English
• ISSNs: 1096-6080

Abstract

Abstract: Seizure liability remains a significant cause of attrition in drug discovery and development, leading to loss of competitiveness, delays, and increased costs. Current detection methods rely on observations made in in vivo studies intended to support clinical trials, such as tremors or other abnormal movements. These signs could be missed or misinterpreted; thus, definitive confirmation of drug-induced seizure requires a follow-up electroencephalogram study. There has been progress in in vivo detection of seizure using automated video systems that record and analyze animal movements. Nonetheless, it would be preferable to have earlier prediction of seizurogenic risk that could be used to eliminate liabilities early in discovery while there are options for medicinal chemists making potential new drugs. Attrition due to cardiac adverse events has benefited from routine early screening; could we reduce attrition due to seizure using a similar approach? Specifically, microelectrode arrays could be used to detect potential seizurogenic signals in stem-cell-derived neurons. In addition, there is clear evidence implicating neuronal voltage-gated and ligand-gated ion channels, GPCRs and transporters in seizure. Interactions with surrounding glial cells during states of stress or inflammation can also modulate ion channel function in neurons, adding to the challenge of seizure prediction. It is timely to evaluate the opportunity to develop an in vitro assessment of seizure linked to a panel of ion channel assays that predict seizure, with the aim of influencing structure-activity relationship at the design stage and eliminating compounds predicted to be associated with pro-seizurogenic state.