Animal Models Of Epilepsy

These are normally based on the use of either electrical stimulation or chemical convulsants. When applied generally, i.e. an electric shock to the whole brain or convulsants injected systemically, the resulting convulsions are indicative of generalised seizures. If they are applied locally to specific brain areas, the same approaches induce activity indicative of partial seizures. Also some animals can be bred in which seizures either occur spontaneously or can be induced easily by appropriate sensory stimulation.

MODELS OF GENERALISED SEIZURES (1) Electric shock

In the maximal electric shock (MES) test a supramaximal stimulus is applied bilaterally through corneal or auricular electrodes to induce tonic hind limb extension in rats or

THE EPILEPSIES (a) Normal

(c) Generalised seizure (petit mal) — absence seizure type zrmm^z

(b) Generalised seizure (grand mal) — tonic-clonic type

(d) Partial seizure

Figure 16.1 EEG patterns in human epilepsies. Electroencephalograms are shown for, a normal subject (a), those suffering from general tonic-clonic seizures (grand mal, (b)), generalised absence seizures (petit mal, (c)), and partial seizures (d). Spikes are seen in both right- and left-sided leads from all three cortical areas, frontal (F), temporal (T) and occipital (C) in the generalised seizures (b, c) but only in the occipital leads in the example of partial seizures (d). In the EEG recorded during the generalised tonic-clonic seizure the normal tracing (1) is followed by the onset of the tonic phase (2), the clonic (convulsive) phase 3 and post-convulsive coma 4. The typical 3 s"1 spike and wave discharge of petit mal (c) may be seen during routine recording or induced by procedures such as hyperventilation but the spiking of grand mal and partial epilepsy is only seen during seizures. (Reproduced from Eliesson et al (1978), Neurological Pathophysiology, 2nd edn, Oxford University Press, New York with permission)

mice. Anticonvulsant activity is determined by measuring the dose of drug required to protect 50% of the stimulated animals (ED or PD50) and is predictive of efficacy in TCS.

(2) Chemical convulsants

A number of different chemicals have been used including GABA antagonists such as bicuculline or picrotoxin. Strychnine convulsions have no predictive value since they arise through antagonism of spinal (glycine-mediated) rather than cortical inhibition. The most commonly used agent is pentylenetetrazol (PTZ), also called leptazol. Anticonvulsant activity is again assessed as the dose required to protect 50% of animals, usually mice, against the clonic seizures induced by a dose of PTZ that would otherwise produce them in almost every mouse injected, the so-called CD97 (convulsive dose in

97% of animals). The absence of a marked tonic component to the seizure may be significant since the ability to protect animals against PTZ convulsions is predictive of a drug's potential efficacy in absence seizures rather than TCS, despite the fact that PTZ causes convulsions.

The anticonvulsant activity of a drug may also be evaluated by measuring its ability to raise the convulsive threshold, i.e. the amount of applied current or infused PTZ required to just evoke a seizure. Comparison of the efficacy of drugs in the threshold and maximal seizure tests may distinguish between their abilities to raise seizure threshold or reduce seizure spread and development.

MODELS OF PARTIAL SEIZURES

Partial seizure activity can be induced by the localised application of chemicals such as cobalt or alumina to the cortex or the injection of chemicals such as PTZ or kainic acid directly into particular brain areas like the hippocampus.

(4) Kindling

If a subconvulsive stimulus is applied, generally in rats, at regular intervals, e.g. daily for some two weeks to a specific brain area, especially the amygdala or hippocampus, then eventually full localised (partial) or secondary generalised seizures develop. A similar effect can be obtained by the repeated localised injection of subconvulsive doses of some convulsants. The ability of a drug to reduce the kindled seizure itself may be indicative of value in partial seizure but if it slows the actual development of kindling that may indicate some ability to retard epileptogenesis.

SPONTANEOUSLY EPILEPTIC (GENETIC) ANIMALS

Various animals show spontaneous epilepsy or seizures that can be readily induced by sensory stimulation (see Jobe et al. 1991). Tottering mice display seizures that resemble absence attacks behaviourally, in their EEG pattern and response to drugs. DBA/2 mice show reflex seizures to audiogenic stimuli while photically-induced seizures can be obtained in the Senegalese baboon, Papiopapio, which are similar to generalised tonic-clonic epilepsy.

PREDICTIVE VALUE

It has become clear that drugs which are effective in protecting mice against PTZ are effective in absence seizures while those able to control the tonic response to maximal electroshock are effective in tonic-clonic seizure. Some drugs are effective in only one test and clinical condition whilst a few are active in both (Table 16.1). Experimental focal seizures are indicative of partial seizures.

It could be argued that an antiepileptic drug should really stop the development of epilepsy, i.e. epileptogenesis, and not merely control seizures which would make them just anticonvulsant. If the development of kindling reflects the process of epilepto-genesis then drugs effective against its progression should stop the development of

Table 16.1 Comparison of the experimental and clinical activities of established antiepileptic drugs

Activity against Effectiveness convulsions induced by clinically in

Activity against Effectiveness convulsions induced by clinically in

Table 16.1 Comparison of the experimental and clinical activities of established antiepileptic drugs

Electroshock

Pentylene tetrazol

Clonic-tonic seizures

Absence seizures

Phenytoin

++

+

Carbamazepine

++

+

Phenobarbitone

+(+)

+

(+)

Na valproate

+

+

+

+

Clonazepam

(+)

++

(+)

+

Ethosuximide

+

The data for the experimental studies gives a semi-quantitative guide to relative activities based on ED50 values, i.e. ++ = active, + = some effect, — = not active at non-toxic doses. Clinical comparisons are not related to recommended doses but simply indicate whether a drug is effective (+) or not ( —). Generally, drugs that are to be used clinically to control tonoclonic seizures control electroshock but not pentylenetetrazol-induced convulsions in rats and mice, whilst the converse applies to drugs effective in absence seizures. Na valproate is effective in both experimental models and is used in both clinical conditions, although in all cases higher doses have to be used than for any other drug.

Notes:

The data for the experimental studies gives a semi-quantitative guide to relative activities based on ED50 values, i.e. ++ = active, + = some effect, — = not active at non-toxic doses. Clinical comparisons are not related to recommended doses but simply indicate whether a drug is effective (+) or not ( —). Generally, drugs that are to be used clinically to control tonoclonic seizures control electroshock but not pentylenetetrazol-induced convulsions in rats and mice, whilst the converse applies to drugs effective in absence seizures. Na valproate is effective in both experimental models and is used in both clinical conditions, although in all cases higher doses have to be used than for any other drug.

human seizures. Phenytoin and carbamazepine do not stop the development of kindling, although acutely they reduce the fully kindled seizure, and in studies of posttraumatic epilepsy following brain damage in humans (car accidents) these drugs stop the appearance of seizures in the first week or so but do not control epileptogenesis, since seizures can develop subsequently in those patients after therapy has stopped. Generally drugs that increase GABA function or block NMDA receptors retard kindling.

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