Can We Panelize Seizure?

Authors

• Ruth Roberts, ApconiX, Alderley Park, SK10 4TG, UK.
• Simon Authier, Charles River Laboratories, Quebec, H7V 4B3, Canada.
• R Daniel Mellon, US Food and Drug Administration, Silver Spring, Maryland 20993.
• Michael Morton, ApconiX, Alderley Park, SK10 4TG, UK.
• Ikuro Suzuki, Tohoku Institute of Technology, Sendai, 980-8577, Japan.
• Ronald B. Tjalkens, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523.
• Jean-Pierre Valentin, UCB Biopharma SRL, Early Solutions, Development Science, Investigative Toxicology, Chemin du Foriest, B-1420, Braine-l'Alleud, Belgium.
• Jennifer B. Pierson, Health and Environmental Sciences Institute, Washington, District of Columbia 20005.

Document Type

Article

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.

Keywords

CNS, MEA, drug development, in vitro models, induced pluripotent stem cells, ion channels, neuron, neurotoxicology, regulatory sciences, seizure

Medical Subject Headings

Animals; Cells, Cultured; Electroencephalography; Humans; Microelectrodes; Neurons; Seizures (chemically induced, diagnosis)

Publication Date

1-6-2021

Publication Title

Toxicological sciences : an official journal of the Society of Toxicology

E-ISSN

1096-0929

Volume

179

Issue

1

First Page

3

Last Page

13

PubMed ID

33165543

Digital Object Identifier (DOI)

10.1093/toxsci/kfaa167

Recommended Citation

Roberts, Ruth; Authier, Simon; Mellon, R Daniel; Morton, Michael; Suzuki, Ikuro; Tjalkens, Ronald B.; Valentin, Jean-Pierre; and Pierson, Jennifer B., "Can We Panelize Seizure?" (2021). Translational Neuroscience. 2508.
https://scholar.barrowneuro.org/neurobiology/2508