Genetically epilepsy-prone rats (GEPRs) and DBA/2 mice: Two animal models of audiogenic reflex epilepsy for the evaluation of new generation AEDs.

This review summarizes the current knowledge about DBA/2 mice and genetically epilepsy-prone rats (GEPRs) and discusses the contribution of such animal models on the investigation of possible new therapeutic targets and new anticonvulsant compounds for the treatment of epilepsy. Also, possible chemical or physical agents acting as proconvulsant agents are described. Abnormal activities of enzymes involved in catecholamine and serotonin synthesis and metabolism were reported in these models, and as a result of all these abnormalities, seizure susceptibility in both animals is greatly affected by pharmacological manipulations of the brain levels of monoamines and, prevalently, serotonin.

Molecular targets for antiepileptic drug development.

This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the alpha subunits of voltage-gated Na+ channels and also T-type voltage-gated Ca2+ channels) or influence GABA-mediated inhibition. Recently, alpha2-delta voltage-gated Ca2+ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets.

Glutamate metabotropic receptors as targets for drug therapy in epilepsy.

Metabotropic glutamate (mGlu) receptors have multiple actions on neuronal excitability through G-protein-linked modifications of enzymes and ion channels. They act presynaptically to modify glutamatergic and gamma-aminobutyric acid (GABA)-ergic transmission and can contribute to long-term changes in synaptic function. The recent identification of subtype-selective agonists and antagonists has permitted evaluation of mGlu receptors as potential targets in the treatment of epilepsy.

The 'glial' glutamate transporter, EAAT2 (Glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings.

The excitatory amino acid transporters (EAAT) removes neurotransmitters glutamate and aspartate from the synaptic cleft. Most CNS glutamate uptake is mediated by EAAT2 into glia, though nerve terminals show evidence for uptake, through an unknown transporter. Reverse-transcriptase PCR identified the expression of EAAT1, EAAT2, EAAT3 and EAAT4 mRNAs in primary cultures of mouse cortical or striatal neurones.

Regional expression of multidrug resistance genes in genetically epilepsy-prone rat brain after a single audiogenic seizure.

Purpose: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood-brain barrier. Recent evidence suggests that P-gp-mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic seizure.

Novel quinolinone-phosphonic acid AMPA antagonists devoid of nephrotoxicity.

We reported previously the synthesis and structure-activity relationships (SAR) in a series of 2-(1H)-oxoquinolines bearing different acidic functions in the 3-position. Exploiting these SAR, we were able to identify 6,7-dichloro-2-(1H)-oxoquinoline-3-phosphonic acid compound 3 (S 17625) as a potent, in vivo active AMPA antagonist. Unfortunately, during the course of the development, nephrotoxicity was manifest at therapeutically effective doses.

Group III mGlu receptor agonists potentiate the anticonvulsant effect of AMPA and NMDA receptor block.

We report the anticonvulsant action in DBA/2 mice of two mGlu Group III receptor agonists: (R,S)-4-phosphonophenylglycine, (R,S)-PPG, a compound with moderate mGlu8 selectivity, and of (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid, ACPT-1, a selective agonist for mGlu4alpha receptors. Both compounds, given intracerebroventricularly at doses which did not show marked anticonvulsant activity, produced a consistent shift to the left of the dose-response curves (i.e.

Implications for neuroprotective treatments.

Pharmacological neuroprotection against the consequences of seizures can be considered as primary neuroprotection where the object is to diminish the initial insult by suppressing the seizure activity or diminishing the associated ionic fluxes (of which the entry of Na+ and Ca2+ are the most significant), and secondary neuroprotection where the target is some later event in the chain linking ionic changes to altered brain morphology or function. Thus primary neuroprotection is provided by antiepileptic drugs and compounds acting on voltage-sensitive Na+ and Ca2+ channels or on glutamate receptors (NMDA, AMPA/KA or Group I metabotropic). Secondary neuroprotection may be a result of acting on the cascade leading to necrosis (e.

Concept of activity-induced cell death in epilepsy: historical and contemporary perspectives.

Selective neuronal loss following status epilepticus was first described just under 100 years ago. The acute pathology following status epilepticus was shown to be 'ischemic cell change' and was assumed to arise through hypoxia/ischemia. Less than 30 years ago it was proposed, from experiments in primates, that the selective neuronal loss in hippocampus and cortex resulted from the abnormal electrical discharges.