title: The emerging role of in vitro electrophysiological methods in CNS safety pharmacology.
abstract: Adverse CNS effects account for a sizeable proportion of all drug attrition cases. These adverse CNS effects are mediated predominately by off-target drug activity on neuronal ion-channels, receptors, transporters and enzymes - altering neuronal function and network communication. In response to these concerns, there is growing support within the pharmaceutical industry for the requirement to perform more comprehensive CNS safety testing prior to first-in-human trials. Accordingly, CNS safety pharmacology commonly integrates several in vitro assay methods for screening neuronal targets in order to properly assess therapeutic safety. One essential assay method is the in vitro electrophysiological technique - the 'gold standard' ion channel assay. The in vitro electrophysiological method is a useful technique, amenable to a variety of different tissues and cell configurations, capable of assessing minute changes in ion channel activity from the level of a single receptor to a complex neuronal network. Recent advances in automated technology have further expanded the usefulness of in vitro electrophysiological methods into the realm of high-throughput, addressing the bottleneck imposed by the manual conduct of the technique. However, despite a large range of applications, manual and automated in vitro electrophysiological techniques have had a slow penetrance into the field of safety pharmacology. Nevertheless, developments in throughput capabilities and in vivo applicability have led to a renewed interest in in vitro electrophysiological techniques that, when complimented by more traditional safety pharmacology methods, often increase the preclinical predictability of potential CNS liabilities.
authors.affiliation: CiToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Accardi
authors.affiliation: Department of Toxicology, Purdue Pharma L.P., Cranbury, NJ 08512, USA.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Pugsley
authors.affiliation: CiToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada.
authors.forename: Roy
authors.initials: R
authors.lastname: Forster
authors.affiliation: Unit of Pharmacology, Faculty of Veterinary Medicine, Université de Montréal, P.O. Box 5000, St.-Hyacinthe, QC J2S 7C6, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Troncy
authors.affiliation: CiToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: CiToxLAB North America, 445 Armand Frappier, Laval, QC H7V 4B3, Canada. Electronic address: authiers@ca.citoxlab.com.
authors.forename: Simon
authors.initials: S
authors.lastname: Authier
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects*; D002493:Central Nervous System Diseases / Q000139:chemically induced*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D004569:Electroencephalography / Q000187:drug effects; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D006801:Humans; D008954:Models, Biological; D012449:Safety; D012640:Seizures / Q000139:chemically induced
keywords: Animal models; Brain slice models; Central nervous system; EEG; Electrophysiology; In vitro; Memory loss; Receptor profile screening; Seizure