Do proconvulsants modify or halt epileptogenesis? Pentylenetetrazole is ineffective in two rat models of temporal lobe epilepsy

Abstract

In patients at risk of developing epilepsy after an initial precipitating injury to the brain, the epileptogenic latent period may offer a window of opportunity for initiating potential antiepileptogenic therapy in an attempt to prevent epilepsy from developing. One potential target for antiepileptogenesis is the development of neuronal hyperexcitability during the latent period. Surprisingly, some recent studies in models of temporal lobe epilepsy (TLE) have suggested that proconvulsant drugs could have favourable effects on epileptogenesis, resulting in the proposal of pursuing proconvulsant prophylaxis for epileptogenesis. In the present study, we evaluated this provocative hypothesis by experiments with the GABA(A) receptor antagonist pentylenetetrazole (PTZ) in two TLE models, the intrahippocampal kainate model and the lithium-pilocarpine model in rats. First, we repeatedly determined the PTZ seizure threshold by i.v. infusion of the convulsant during the latent period following intrahippocampal kainate. In line with recent experiments in the lithium-pilocarpine model, the PTZ seizure threshold was significantly decreased over several days following status epilepticus. We then studied whether prolonged infusion of a proconvulsant dose of PTZ at different times after kainate or pilocarpine affected the development of epilepsy. PTZ did not prevent the development of spontaneous recurrent seizures and did not decrease their frequency or severity, but exerted only a moderate disease-modifying effect in that spontaneous seizures in the kainate model were significantly shortened. These data indicate that administration of proconvulsant drugs such as PTZ during the latent period following SE is not a promising strategy for preventing epilepsy.

A novel prodrug‐based strategy to increase effects of bumetanide in epilepsy

“…We have recently shown in rats that the threshold to seizures induced by the GABA A receptor antagonist pentylenetetrazol (PTZ) decreases during the latent period following status epilepticus (SE) induced by either pilocarpine or kainate, indicating that the PTZ seizure threshold may be used as a biomarker of changes in GABAergic transmission during epileptogenesis . In the present experiments in mice, before administration of pilocarpine, average PTZ seizure thresholds in controls ranged from 55mg/kg PTZ for the first myoclonic twitch to 112mg/kg for tonic hindlimb extension (Fig ), which was often followed by death of the animals.…”

Refinement of a model of acquired epilepsy for identification and validation of biomarkers of epileptogenesis in rats

“…Furthermore, we have previously shown that the sensitivity of the BLA to electrical stimulation is not affected by the estrous cycle in rats [15] so that the stage of the estrous cycle was not determined in the present experiments. Similarly, the PTZ seizure threshold is not affected by the estrous cycle in rats [16,17].…”

The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy

“…Furthermore, although the estrous cycle is thought to affect seizure threshold [198,199], thus causing variability when using females, this is not true for all types of seizure threshold in rodents. For instance, PTZ seizure thresholds determined by timed intravenous infusion of this convulsant is not affected by the estrous cycle in rodents, while estrous cycle-dependent changes (and significant differences between females and males) were found for bicuculline seizure thresholds [200,201]. Similarly, the ADT in amygdala kindled female rats did not change significantly during the estrous cycle [202], while small but statistically significant changes were reported for electroshock seizure thresholds (EST) in rats [203].…”