Chapter

Antiepileptogenesis, Plasticity of AED Targets, Drug Resistance, and Targeting the Immature Brain

Heinz Beck and Yoel Yaari

in Jasper's Basic Mechanisms of the Epilepsies

Fourth edition

Published on behalf of ©Jeffrey L. Noebels, Massimo Avoli, Michael A. Rogawski, Richard W. Olsen, and Antonio V. Delgado-Escueta

Published in print July 2012 | ISBN: 9780199746545
Published online April 2013 | e-ISBN: 9780199322817 | DOI: http://dx.doi.org/10.1093/med/9780199746545.003.0083

Series: Contemporary Neurology Series

Antiepileptogenesis, Plasticity of AED Targets, Drug Resistance, and Targeting the Immature Brain

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The cellular basis of epileptic seizures consists of high-frequency, synchronized discharges of neuronal ensembles. The ultimate goal of all antiepileptic therapies is to prevent the occurrence of such episodes or to substantially attenuate their severity. To this end, a multitude of antiepileptic compounds have been developed that are currently in clinical use. However, seizures remain uncontrolled by carefully monitored drug treatment in a substantial portion (∼30%) of epilepsy patients. Therefore, a better understanding of the mode of action of different antiepileptic drugs is mandatory, along with an improved understanding of why these compounds fail in some epilepsy patients, with the ultimate goal of developing new therapeutic avenues. So far, two hypotheses have been advanced to account for the cellular basis of pharmacoresistance in chronic epilepsy. The first hypothesis proposes that pharmacoresistance involves an upregulation of multidrug transporters at the blood-brain barrier. This upregulation limits the access of antiepileptic drugs to the brain parenchyma and therefore leads to a reduced drug concentration at the respective drug target. Because multidrug transporter proteins are of central importance to this hypothesis, it has been termed the transporter hypothesis. The second hypothesis contends that the molecular targets of antiepileptic drugs are modified in chronic epilepsy. Consequently, they are less sensitive to these compounds. This hypothesis has been named the target hypothesis.1,2 Clearly, these two hypotheses are not mutually exclusive. Rather, the underlying mechanisms may coexist and perhaps even act in synergy. The subject of this chapter is the target hypothesis. We describe the molecular mechanisms that alter the targets of antiepileptic drugs and how these mechanisms may interact with altered drug transporter function to cause pharmacoresistance.

Chapter.  5420 words. 

Subjects: Neurology

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