The MES and scPTZ tests

The MES and scPTZ seizure models continue to represent the two most widely used animal seizure models employed in the search for new AEDs [5,8,9] and presently remain as the primary screens of the Anticonvulsant Screening Project (Fig. 8.1). As mentioned above, Merritt and Putnam successfully employed the MES test in a systematic screening programme to identify phenytoin [6]. This observation when coupled with the subsequent success of phenytoin in the clinical management of generalized tonic-clonic seizures provided the validation necessary to consider the MES test as a reasonable model of human generalized tonic-clonic seizures. In 1944, Everett and Richards [10] demonstrated that PTZ-induced seizures could be blocked by trimethadione and phenobarbital but not by phenytoin. A year later, Lennox demonstrated that trimethadione was effective in decreasing or preventing petit mal attacks in 50 patients but was ineffective or worsened grand mal attacks in 10 patients [11], Trimethadione's success in the clinic and its ability to block threshold seizures induced by PTZ provided the necessary correlation to establish the PTZ test as a model of petit mal or generalized absence seizures. With these observations, the current era of AED screening using the MES and scPTZ tests was launched.

The MES and scPTZ tests are routinely conducted with either mice or rats. For the MES test, individual animals receive an electrical stimulus that is delivered through either corneal or pinneal electrodes for 0.2 s duration. The stimulus is of sufficient intensity (e.g. 50 mA in mice and 150 mA in rats) to induce a tonic extension seizure characterized by hindlimb extension. This stimulus intensity is typically five to 10 times greater than the threshold current necessary to evoke a maximal seizure. An investigational drug is said to offer protection in the MES test if it displays an ability to block the hindlimb tonic extensor component of the seizure.

In the scPTZ test, PTZ is administered subcutaneously in a dose sufficient to produce a minimal clonic seizure of the vibrissae and/or forelimbs that persists for at least 5 s. A drug is said to be effective in the scPTZ test if it is able to block the minimal clonic seizure described above. It is important to note that higher doses of PTZ can produce myoclonic jerks, repeated clonic seizures of the vibrissae, forelimbs and hindlimbs without loss of righting reflex, clonic seizures of the limbs with loss of righting reflex and loss of righting reflex followed by tonic extension of the forelimbs and hindlimbs [12], This is important to note because these different endpoints have been shown to be associated with markedly different pharmacological profiles [12,13]. For example, ethosuximide and pheny-

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