Modeling to Test New Therapies

Pharmacotherapy

Beginning with studies of phenytoin, investigations in animal models have been used to determine the efficacy and safety of new antiepileptic compounds before they are tried in patients. Animal models of epileptic seizures have been indispensable for this purpose. With one exception (leve-tiracetam), however, all potential new antiepileptic compounds have been screened against only two mouse models of epileptic seizures: maximal electroshock and subcutaneous Metrazol (Levy et al., 2002). Undoubtedly testing drugs in these models of generalized tonic-clonic seizures and absence seizures, respectively, has resulted in identification of many drugs effective against epilepsies associated with these two seizure types. However, this approach has been less useful in the discovery of drugs for treating other seizure types, particularly focal seizures and atonic seizures. Consequently epilepsy associated with focal and atonic seizures are often medically refractory. It is likely that many compounds that might have been excellent for preventing focal and atonic ictal events were discarded because they did not have anticonvulsant or antiabsence properties. These two acute seizure mouse models continue to be used for drug screening because large numbers of compounds can be screened inexpensively. In contrast it is very expensive to screen large numbers of compounds against chronic models (e.g., the amygdala kindling model of MTLE). There is therefore a great need to develop new animal models of those seizure types that are particularly refractory to current pharmacotherapy that could be cost-effectively used for drug screening. Development of model systems based on surrogate markers might possibly fill this role.

Alternative Therapies

Alternative treatments for epilepsy also benefit from animal research. Vagus nerve stimulation (VNS), for instance, was first investigated with acute seizures in dogs and then with chronic epilepsy in monkeys before it was tried in humans (Schachter and Wheless, 2002). Animal research is also playing an important role in developing the techniques of deep brain stimulation as a treatment for epilepsy. Epilepsy surgery, gamma knife surgery, and the ketogenic diet (KD) have been used effectively in patients without preliminary studies in animals. However, animal research continues to be of value in our efforts to understand how these therapeutic interventions work, what might be done to improve them, and which patients are most likely to benefit from their use. Identifying appropriate animal models for testing therapeutic interventions is a prime concern. For example, because KD is principally used in children, understanding and improving KD-based approaches require comparable immature brain experimental animal models (Stafstrom and Rho, 2004).

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Good Carb Diet

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