Background:  The NINDS Epilepsy Therapy Screening Program (ETSP) is a preclinical screening program that provides researchers the opportunity to screen potential therapeutic agents in established rodent seizure models. Since its establishment, the ETSP has played a role in the development of several FDA-approved epilepsy drugs.

You Will Learn:  This webinar broadly discusses the scope of the ETSP and new models and assays available at the University of Utah.

Speaker Bio:  This webinar was presented by Dr. Cameron Metcalf, a Research Assistant Professor in Pharmacology and Toxicology at the University of Utah. He is also a Co-Investigator and the Associate Director of the Anticonvulsant Drug Development Program.  Dr. Metcalf’s primary research interests include the evaluation and advancement of novel therapies for the treatment of epilepsy and pain.

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Audience Q&A with Dr. Metcalf

In the intrahippocampal model, what areas do you record the EEG from?

So I would refer you to our colleagues at SynapCell for greater detail; they published their pharmacology and their methodology recently. But these recordings are deaf electrodes in the hippocampus. And since I don’t have any direct involvement with the actual performance of that model, I can’t say more than that. But I can refer you to their publications.

In the testing scheme which you showed at the beginning of your presentation, is it a step-wise process to go from the identification to the differentiation step? Or, how do you determine when a compound can move into the differentiation?

Sure. Thank you for the question. So one thing that I’ll say is that the decisions to advance compounds from one part of the testing scheme to another … we’re not always privy to those, and so I would defer to my colleagues at NINDS for specific examples.

What I can say generally is that the scheme is designed for it to be step-wise, meaning that as a compound advances through the identification phase, it would be a candidate to move toward the differentiation phase. What you might also envision is that while there are many compounds that could initially be tested in identification, not all those compounds have been advanced.

And so, there are some benchmarks and some go/ no-go decisions if you will, that help the ETSP in advancing compounds. There’s a lot of different factors that can come into play, and not all participants enter the program in equivalent ways. Some have to enter and exit for various reasons. Others may be limited in what their desires are to obtain information from the program. So I think it really varies, but in a very broad sense, it is intended to be step-wise.

Which amygdala nucleus is injected with kainic acid?

The model was designed around injection of the basolateral amygdala with kainic acid. And I should mention, this is also a good opportunity to highlight that we do have an upcoming manuscript that’s being prepared that will describe some of our methodologies.

Do you have any preliminary results in the intra-amygdala kainic acid model in mice, in terms of the seizure frequency and progression of the spontaneous seizures?

Yeah, great question, and again I would refer you to a paper that we will have forthcoming. We’ve also presented these at AES in the past. What I can say very broadly is that we do see variable seizure frequency similar to what I described for the rat kainate model. In a very general sense, we see on average about one seizure per day, but that really can vary quite dramatically. We can have animals that have a very high seizure burden, and we can have other animals that don’t have as many seizures, or seizures at all. And so we’re trying to find the best way to optimize our use of this model, and that’s going to be something that we’re going to continue to look at going forward.

When you do the tolerability toxicity assays, are you only working with models to look at motor activity, or are there other models that you look at for other types of toxicity?

Yeah, great question. This is something that we’ve thought a lot about recently. Historically, the models that we used to look at tolerability were really geared toward motor activity, and so that would include the rotarod assay in mice. We used a modified open field observational assay in rat. And we also used an open field automated locomotor open field assay.

However, in recent years, we’ve also brought on board a modified Irwin test. And while this isn’t as comprehensive as many you may be familiar with, it continues to be largely geared toward motor activity, but it also does allow us opportunity to look at other potential means of toxicity, such as autonomic, audio-visual and others. And so, this is helping us, but for those of you that work with rodent behavior, there’s only so much we can do, I think, to look at tolerability and be predictive of what happens in the clinical setting. But we have recently expanded our abilities to look at tolerability, particularly in rats.

What mice strain do you use for the acute seizure, the 6 Hz instead of epilepticus, because different strains can have drastic changes with regards to the severity of this?

Wonderful question, thank you, and this is also something we think a lot about. It does vary by model, so for 6 Hz and MES we use the CF-1 mouse strain from Charles River. For the corneal kindling assay, we have used the CF-1 animal in the past, however recently we’ve gone to the Charles River C57 black 6 model of mouse. For the TMEV assay, and for intra-amygdala kainate, we use C57s from Jackson. And so it does vary, but most directly to answer your question, we use the CF-1 mouse for our acute seizure assays.

But I do take the point that there are notable differences, not only in seizures but also in seizure pharmacology.