Identification of New Antiseizure Medication Candidates in Preclinical Animal Studies.

Epilepsy is a multifactorial neurologic disease that often leads to many devastating disabilities and an enormous burden on the healthcare system. Until now, drug-resistant epilepsy has presented a major challenge for approximately 30% of the epileptic population. The present article summarizes the validated rodent models of seizures employed in pharmacological researches and comprehensively reviews updated advances of novel antiseizure candidates in the preclinical phase. Newly discovered compounds that demonstrate antiseizure efficacy in preclinical trials will be discussed in the review. It is inspiring that several candidates exert promising antiseizure activities in drug-resistant seizure models. The representative compounds consist of derivatives of hybrid compounds that integrate multiple approved antiseizure medications, novel positive allosteric modulators targeting subtype-selective γ-Aminobutyric acid type A receptors, and a derivative of cinnamamide. Although the precise molecular mechanism, pharmacokinetic properties, and safety are not yet fully clear in every novel antiseizure candidate, the adapted approaches to design novel antiseizure medications provide new insights to overcome drug-resistant epilepsy.

Paradoxical Anticonvulsant Effect of Cefepime in the Pentylenetetrazole Model of Seizures in Rats.

Many ß-lactam antibiotics, including cephalosporins, may cause neurotoxic and proconvulsant effects. The main molecular mechanism of such effects is considered to be γ-aminobutyric acid type a (GABAa) receptor blockade, leading to the suppression of GABAergic inhibition and subsequent overexcitation. We found that cefepime (CFP), a cephalosporin, has a pronounced antiepileptic effect in the pentylenetetrazole (PTZ)-induced seizure model by decreasing the duration and severity of the seizure and animal mortality. This effect was specific to the PTZ model. In line with findings of previous studies, CFP exhibited a proconvulsant effect in other models, including the maximal electroshock model and 4-aminopyridine model of epileptiform activity, in vitro. To determine the antiepileptic mechanism of CFP in the PTZ model, we used whole-cell patch-clamp recordings. We demonstrated that CFP or PTZ decreased the amplitude of GABAa receptor-mediated postsynaptic currents. PTZ also decreased the current decay time constant and temporal summation of synaptic responses. In contrast, CFP slightly increased the decay time constant and did not affect summation. When applied together, CFP prevented alterations to the summation of responses by PTZ, strongly reducing the effects of PTZ on repetitive inhibitory synaptic transmission. The latter may explain the antiepileptic effect of CFP in the PTZ model.

Molecular and neurochemical substrates of the audiogenic seizure strains: The GASH:Sal model.

PURPOSE: Animal models of audiogenic epilepsy are useful tools to understand the mechanisms underlying human reflex epilepsies. There is accumulating evidence regarding behavioral, anatomical, electrophysiological, and genetic substrates of audiogenic seizure strains, but there are still aspects concerning their neurochemical basis that remain to be elucidated. Previous studies have shown the involved of γ-amino butyric acid (GABA) in audiogenic seizures. The aim of our research was to clarify the role of the GABAergic system in the generation of epileptic seizures in the genetic audiogenic seizure-prone hamster (GASH:Sal) strain. MATERIAL AND METHODS: We studied the K+/Cl- cotransporter KCC2 and ß2-GABAA-type receptor (GABAAR) and ß3-GABAAR subunit expressions in the GASH:Sal both at rest and after repeated sound-induced seizures in different brain regions using the Western blot technique. We also sequenced the coding region for the KCC2 gene both in wild- type and GASH:Sal hamsters. RESULTS: Lower expression of KCC2 protein was found in GASH:Sal when compared with controls at rest in several brain areas: hippocampus, cortex, cerebellum, hypothalamus, pons-medulla, and mesencephalon. Repeated induction of seizures caused a decrease in KCC2 protein content in the inferior colliculus and hippocampus and an increase in the pons-medulla. When compared to controls, the basal ß2-GABAAR subunit in the GASH:Sal was overexpressed in the inferior colliculus, rest of the mesencephalon, and cerebellum, whereas basal ß3 subunit levels were lower in the inferior colliculus and rest of the mesencephalon. Repeated seizures increased ß2 both in the inferior colliculus and in the hypothalamus and ß3 in the hypothalamus. No differences in the KCC2 gene-coding region were found between GASH:Sal and wild-type hamsters. CONCLUSIONS: These data indicate that GABAergic system functioning is impaired in the GASH:Sal strain, and repeated seizures seem to aggravate this dysfunction. These results have potential clinical relevance and support the validity of employing the GASH:Sal strain as a model to study the neurochemistry of genetic reflex epilepsy. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".