Differential effects of various xanthines on pentylenetetrazole-induced seizures in rats: an EEG and behavioural...

The present study deals with the EEG (electroencephalogram) and behavioural effects of a subconvulsant dose (30 mg/kg i.p.) of pentylenetetrazole in freely moving rats pretreated (100 mg/kg p.o., 1 h before pentylenetetrazole) with two classic (theophylline and caffeine) and two new (enprofylline and isbufylline) xanthines. In rats treated with vehicle, pentylenetetrazole caused a slight desynchronization of the EEG, characterized by periods of 'wave discharges', and 'spike-and-wave discharge complexes'. In rats pretreated with xanthines (theophylline or caffeine) pentylenetetrazole produced a dramatic increase in ictal seizures with the appearance of continuous spikes; concomitantly animals experienced myoclonic jerks (100%) and in some cases (ca. 20%) the animals died. In contrast, in enprofylline-pretreated rats, pentylenetetrazole induced only brief periods of wave discharges and spike-and-wave discharge complexes whose duration was significantly reduced compared to that of controls, although these discharges were associated with mild epileptic behaviour. When isbufylline-pretreated rats were challenged with pentylenetetrazole, the EEG was characterized by a short run of wave discharges (whose duration was shorter than that of other groups). No enprofylline- or isbufylline-treated rats developed seizures or died. In conclusion, only xanthines with strong adenosine A1 receptor antagonism (theophylline and caffeine) markedly enhance the EEG and behavioural effects of a subconvulsive dose of pentylenetetrazole. The present experimental approach could be used to evaluate the pro-convulsive potential of new xanthine derivatives.