Animal Models of Seizures and Epilepsy: Past, Present, and Future Role for the Discovery of Antiseizure Drugs

Abstract

The identification of potential therapeutic agents for the treatment of epilepsy requires the use of seizure models. Except for some early treatments, including bromides and phenobarbital, the antiseizure activity of all clinically used drugs was, for the most part, defined by acute seizure models in rodents using the maximal electroshock and subcutaneous pentylenetetrazole seizure tests and the electrically kindled rat. Unfortunately, the clinical evidence to date would suggest that none of these models, albeit useful, are likely to identify those therapeutics that will effectively manage patients with drug resistant seizures. Over the last 30 years, a number of animal models have been developed that display varying degrees of pharmacoresistance, such as the phenytoin- or lamotrigine-resistant kindled rat, the 6-Hz mouse model of partial seizures, the intrahippocampal kainate model in mice, or rats in which spontaneous recurrent seizures develops after inducing status epilepticus by chemical or electrical stimulation. As such, these models can be used to study mechanisms of drug resistance and may provide a unique opportunity for identifying a truly novel antiseizure drug (ASD), but thus far clinical evidence for this hope is lacking. Although animal models of drug resistant seizures are now included in ASD discovery approaches such as the ETSP (epilepsy therapy screening program), it is important to note that no single model has been validated for use to identify potential compounds for as yet drug resistant seizures, but rather a battery of such models should be employed, thus enhancing the sensitivity to discover novel, highly effective ASDs. The present review describes the previous and current approaches used in the search for new ASDs and offers some insight into future directions incorporating new and emerging animal models of therapy resistance.

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

“…13 Lamotrigine and other ASDs, administered during various forms of kindling, have been used to induce pharmacoresistant seizures. 13 Lamotrigine and other ASDs, administered during various forms of kindling, have been used to induce pharmacoresistant seizures.…”

“…13 Lamotrigine and other ASDs, administered during various forms of kindling, have been used to induce pharmacoresistant seizures. Despite the importance and prevalence of this model in preclinical evaluation of novel compounds, 13 and although there have been previously published reports for the evaluation of some prototype compounds, 10,11 this is the first comprehensive evaluation of this model comparing prototype antiseizure compounds. The lamotrigine-resistant amygdala-kindled rat has become an important and useful model for the evaluation of novel compounds with potential activity against pharmacoresistant seizures.…”

“…2 Further, it was observed that tolerance to lamotrigine extended to some sodium channel blockers but not to ASDs with other mechanisms. 12,13 One of the major goals for the development of novel ASDs is to minimize or eliminate side effects at therapeutic doses. 7,8 Further, resistance to one drug can extend to other ASDs, 5,6,10 thus suggesting the potential for this approach as a screening model for drug-resistant epilepsy.…”

2017 WONOEP appraisal: Studying epilepsy as a network disease using systems biology approaches

“…44,45 Even in disorders that have well-characterized genetic etiologies, precision therapies are not curative for seizures. High-throughput omics technologies fit nicely within this paradigm, as they allow unbiased screening for potential targets, for example, by comparing molecular readouts between case and control tissue.…”

An Overview of Non-drug Therapies for the Treatment of Epilepsy

“…At present several animal models are available to study the potential therapeutic agents for the epilepsy treatment and to identify the multiple causes leading to epilepsy [22] . Emergence of highly advanced technologies in imaging and electrophysiology can unravel the neuronal activity and its alteration during and after the epilepsy in brain [23][24][25] .…”