3 Steps to Functional Neurotoxicity Assessment using Microelectrode Arrays

Microelectrode arrays (MEAs) can be used to assess electrical activity in primary cultures and slices of nervous system tissues, and detect the effects of many different classes of compounds. Dr. Tim Shafer, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, at U.S. Environmental Protection Agency shares his experiences ahead of the1st American Predictive Toxicology Summit.

Pharma IQ: What are the limitations of in vitro approaches and how are these best solved?
Dr. Shafer: One limitation of in vitro approaches is the lack of metabolic capacity, especially nervous system preparations. Thus, if a chemical has to be metabolized to be active, it may be missed in screening. One solution to this problem is the incorporation of liver enzyme preparations such as an S9 fraction. If the metabolites of a compound are known, they can be tested directly. Another approach is to use programs that predict possible metabolites.
There are also challenges in understanding the relationship between concentrations of test compound in vitro in the cells and media (e.g. in vitro pharmacokinetics) and how they relate to concentrations in the blood and tissue of interest in vivo.
For screening, understanding this relationship is not critical. However, when trying to predict in vivo effects from in vitro data, characterization of the in vitro toxicokinetics can improve the ability to predict the in vivo effects.
Pharma IQ: What are the latest tools available for the reduction of adverse effects and the successful prediction of long-term toxicity?
Dr. Shafer: There are an increasing numbers of tools available to screen compounds for the potential to cause toxicity and identify those that may ultimately cause adverse effects. In general, approaches where the link between the adverse outcome and the key event in the screening assay are well established and have a better ability to predict toxicity.

Pharma IQ: You will be giving a workshop on Functional Neurotoxicity Assessment using Microelectrode Arrays at the 1st American Predictive Toxicology Summit, can you share some insights of that session with us?
Dr. Shafer: This workshop format will allow for increased interactions between myself and the participants. In addition to providing basics for those who are unfamiliar with this approach, it will highlight our recent experiments using multi-well microelectrode array (MEA) systems to screen a training set of chemicals for their ability to disrupt neuronal function;  this approach demonstrated a very high sensitivity and specificity of MEAs.
I will discuss approaches to classify chemicals according to their profile of disruption of activity on MEAs and how our recent work shows clear separation of GABA-A antagonists that cause seizures from other classes of chemicals.
Finally, I will also present an example of determinations of relative potency within a class of structurally related chemicals (pesticides) and of extrapolation of effective doses between in vitro MEA recordings and in vivo effects on seizures.
Interview by Niamh Madigan, Pharma IQ, www.pharma-iq.com
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