Experimental Seizure Models and New Antiepileptic Drugs

The objective of this programme of work was to study experimental seizure models and new antiepileptic drugs. Initial investigations addressed the contribution of basic animal models of epilepsy to its experimental study. Next, an attempt was made to emphasise the crucial role of neuronal inhibition and excitation in epileptogenesis and to relate these phenomena to the study of novel antiepileptic agents. Finally, the future of epilepsy research, in terms of appropriate strategies for AED development and innovative experimental paradigms was examined. Investigation of basic animal seizure models Of all the experimental seizure models in current laboratory employment, the pentylenetetrazol (PTZ) test, and the maximal (MES) and minimal (Min-ES) electroshock tests are among the most popular by virtue of their simplicity and economy. The primary aim of these studies was to afford a familiarity with these three basic animal seizure models and to validate them as techniques for subsequent use. These studies also incorporated an investigation of concentration-effect relationships with PTZ which attempted to delineate previously observed efficacy problems with this compound in our laboratory. Validation of all three experimental models was satisfactory, with results reflecting those reported in the literature. Although the concentration-effect studies with PTZ afforded a degree of insight into its pharmacokinetics, attempts to provide a suitable explanation for its lack of convulsant action in some animals proved unsuccessful. Antiepileptic drug enhancement of neuronal inhibition Impairment of gamma-aminobutyric acid (GABA)-mediated neuronal inhibition is believed to be one of the fundamental aetiological mechanisms of epileptogenesis. These investigations compared and contrasted the experimental anticonvulsant profiles and mechanisms of action of vigabatrin (VGB) and tiagabine (TGB), two novel AEDs which have been proposed to enhance GABA-mediated inhibition. VGB raised the threshold for induction of tonic seizures, determined by the Min-ES test, but was without effect in the PTZ and MES tests. TGB, in contrast, exhibited anticonvulsant effects against both PTZ- and MES-induced seizures. Drug mechanisms were investigated in isolated brain tissue and in primary cultures of cerebral cortical astrocytes and neurones. Previously reported mechanisms of action of the two drugs were confirmed, with VGB inhibiting GAB A metabolism by an action on GABA-aminotransferase (GABA-T), and TGB blocking GAB A uptake in a non-cell-specific manner. An inhibitory effect of VGB on glutamic acid decarboxylase (GAD) was also verified, and an additional, previously unreported action of the drug on GABA uptake was proposed. Antiepileptic drug attenuation of neuronal excitation Glutamate-induced neuronal excitability and voltage-sensitive calcium influx are believed to be inexorably entwined at all stages of epileptogenesis. These studies compared and contrasted the experimental anticonvulsant profiles and mechanisms of action of nimodipine (NMD) and amlodipine (AML), members of the dihydropyridine (DHP) class of calcium channel blockers which have been proposed as putative AEDs. In single dose, NMD was effective against MES-induced seizures and also raised the tonic seizure threshold, determined by the Min-ES test. Its effects in the MES test appeared to extend Novel strategies for antiepileptic drug development It has been proposed that to satisfactorily address the problem of refractory epilepsy the development of novel antiepileptic agents with similarly novel mechanisms of action is required. Nicotinylalanine (NA) is a newly-synthesised neuroactive compound which is believed to exert its effects by inhibition of the kynurenine pathway, resulting in increased brain concentrations of kynurenic acid, an endogenous antagonist at the glycine recognition site on the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. This study explored the anticonvulsant profile of NA in three standard animal models of seizure. NA protected against PTZ induced seizures in mice in a dose and time dependent manner and was also active in the maximal and minimal electroshock tests. These preliminary results would suggest that NA warrants further investigation as a putative AED. Development of a novel animal model of epilepsy It is now recognised that few, if any, of the existing "animal models of the epilepsies" mirror the condition of chronically recurrent spontaneous seizures which is characteristic of human epilepsy. This study followed the preliminary development of an innovative model of partial epilepsy, proposed to more closely mimic the human condition. This model was characterised by a laser-induced lesion in the rat somatosensory cortex. Production of cortical laser lesions in the rat proved to be a feasible procedure. Histological investigation proposed the lesions to be highly reproducible and to possess cellular characteristics similar to those of disruptive brain insults in man. The lesion did not appear to be intrinsically epileptogenic, nor did the procedure influence the latency to generalised PTZ-induced seizures. Preliminary autoradiographical studies suggested that brain damage associated with the procedure was confined to the lesion tract itself, and that cerebral glucose metabolism was additionally altered in adjacent, otherwise healthy, tissue. Despite possessing several attractive features, the full potential of this model for use in epilepsy research remains to be evaluated