What are WAG/Rij rats?

More information about the WAG/Rij rat as model for human absence epilepsy.

The WAG/Rij model for absence epilepsy

In 1986 it was discovered by us, that rats of the WAG/Rij strain show spontaneous occurring spike-wave discharges in their electroencephalogram (EEG). They consist of bursts with a duration of 1 till 30 seconds (mean duration about 5 sec.) and a spike-wave frequency of 7 till 10 Hz. The number of spike-wave discharges increases with age to 16-18 spike-wave discharges per hour emerge at an age of about six months, adding up to approximately 300 till 400 trains of discharges per day. The sex differences are minimal. A few years earlier it was described by Marguerite Vergnes and Christian Marescaux that a subpopulation of their Wistar rats exhibited the same phenomena.

Valid models?

It is accepted that two genetic rat models - WAG/Rij and GAERS, and perhaps other rat models in the future - are valid models for human absence epilepsy. They have face validity since both in humans and in rats a comparable relationship with the state of vigilance has been found. Moreover, there are clear similarities in behavioural traits during seizures. A minor point is that the differences in ontogeny between man and rats do not contribute to complete face validity and also not the difference in spike frequency.The model has also predictive validity if it correctly predicts the outcomes of interferences in humans, implying no or few false negatives or false positives. One of the methods to predict therapeutic drug actions on human absence seizures is the pre-clinical screening of putative anti-absence compounds for their efficacy in genetic rat models. Many drugs have already been evaluated in the WAG/Rij and GAERS models. The first screening of the pharmacological profile of spike-wave discharges was done with classical anti-epileptic drugs. Ideally, these drugs, which are specifically prescribed for generalised absence epilepsy, should suppress spike-wave discharges. Ethosuximide, valproate and trimethadione were selected as specific anti-absence drugs and all drugs suppressed spike-wave activity. Thus, the model predicts correctly the anti-absence profile of these drugs. Other anti-epileptics such as those for tonic-clonic convulsions, should have no effect upon, or even aggravate, epileptic activity. Diphenylhydantoin and carbamazepine were used as representing anti-convulsant drugs and these drugs triggered a substantial increase in spike-wave discharges. Hence, the WAG/Rij and GAERS model correctly predicts the lack of anti-absence actions, as well as the aggravating effects of these two drugs and also many GABA-mimetics on absences. These data not only suggest that both models have good predictive validity for anti-absence drug, but also that these models suggest equally well that drugs known to aggravate spike-wave discharges might have potentially anti-convulsant properties. To date several new compounds have been evaluated in both strains and are now awaiting confirmation in clinic.

Future

WAG/Rij rats have a bright future since WAG/Rij rats are widely available, healthy and fertile. Many genetic, neurochemical, neurophysiological, and pharmacological studies are still possible.