EVALUATION OF A LOCAL ELECTROSHOCK MODEL FOR SCREENING POTENTIAL ANTI-EPILEPTIC DRUGS

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EVALUATION OF A LOCAL ELECTROSHOCK MODEL FOR SCREENING POTENTIAL ANTI-EPILEPTIC DRUGS

CHAPTER ONE

INTRODUCTION

Background of the study

In spite of the currently available therapeutic arsenal of old and new antiepileptic drugs (AEDs), almost one-third of epileptic patients continue to present seizures that appear to be refractory to all pharmacological schemes (1, 2). Subsequently, there is a substantial need to develop new and more effective AEDs, and numerous compounds are now in preclinical and clinical trials (2, 3).

The choice of appropriate animal models for the initial in vivo testing of a potential anticonvulsant drug is one of the most important steps in the successful search for new AEDs. At present, preclinical animal studies are indispensable in exploring the efficacy and safety of an investigational AED before its introduction in human volunteers (4-7).

Although modern cellular neurophysiological and biochemical approaches have made it possible to identify molecular targets of AEDs, in vitro testing is not likely to replace screening in animal models: on the one hand, in vitro systems cannot model the specific pharmacodynamic actions required for seizure protection since they do not assess the multidimensional parameter space, which includes not only the target molecules but also critical biomolecules that could cause side effects or interfere with the desired activity; on the other hand, in vitro testing does not assess bioavailability, brain accessibility and local delivery to the target. Therefore, only animal test systems can select compounds that are inherently anticonvulsant and are able to access the relevant brain targets (8).

If the purpose of the research is not to study the epileptic phenomenon itself but to screen new AEDs, the animal models fall into two main categories: models of acute seizures (nonepileptic animals induced to have a seizure by an electrical or chemical stimulus) and models of chronic epilepsy (animals induced to have enhanced seizure susceptibility or spontaneous seizures) (8). For practical reasons, experimental research on new AEDs has mostly been carried out on normal mice and rats in which seizures were induced by chemical or electrical means (6, 7). Indeed, with respect to screening purposes, electrically or chemically induced seizures have advantages over most genetic models since seizure-susceptible animal species may lead to an exaggeration of the anticonvulsant potency of a new drug.

1.2 Statement of the problem

Over the years, the maximal electroshock seizure (MES) model has remained one of the gold standards in early stages of testing.

Continuous search for new models closer to the human epilepsy phenomenon, the MES model will persist as the most useful tool at least at the anticonvulsant compound identification stage. Hence, we intend to describe in a single paper all the useful yet dispersed information on performing anticonvulsant screening by MES tests, drawing particular attention to experimental procedures and factors affecting the accuracy of experimental data.

Objectives of the study
To understand the impact of electroshock model on screening anti-epileptic drugs
To understand the relationship between electroshock model and screening potential of anti-epileptic drugs

Research Questions

What is the impact of electroshock model on screening anti-epileptic drugs
What is the relationship between electroshock model and screening potential of anti-epileptic drugs