Assessment of seizure susceptibility in pilocarpine epileptic and nonepileptic Wistar rats and of seizure reinduction with pentylenetetrazole and electroshock models

Abstract

Our findings suggest that the induction of acute seizures with PTZ, but not with MES, in animals pretreated with pilocarpine (regardless of SE induction) might constitute an effective and valuable method to screen AEDs and to study mechanisms involved in pharmacoresistant temporal lobe epilepsy (TLE).

Seizures triggered by pentylenetetrazol in marmosets made chronically epileptic with pilocarpine show greater refractoriness to treatment

“…Even though the antagonism between PTZ and PB does not rely on a competition for the same binding site, the previous PB administration may prompt conformational changes, which might reduce the responsiveness of GABA-A channel to PTZ. However, the efficacy of PB presented here corroborates the anticonvulsant effect on similar combined pilocarpine-PTZ in mice (Tollner et al, 2016) but contrasts with its negligible effect in an equivalent model in rats (Blanco et al, 2009). This divergence might be related to the P-glycoprotein, a drug efflux transporter located in the blood-brain barrier (BBB).…”

“…The boxplots (blue) illustrate median, quartiles, minimum and maximum values. # indicates p ≤ 0.05 according to Kruskal-Wallis. pilocarpine/PTZ protocol), which presented similar profile of partial and generalized seizures in both epileptic and naïve rodents (Blanco et al, 2009). Importantly, this enhanced ictal prone condition might have undermined the efficacy of AEDs, given the suppression of seizures by AEDs was less in the chronic epileptic condition.…”

“…For the first and fifth drug testing sessions the compound was invariably saline, whereas phenobarbital (PB, 40 mg/kg), carbamazepine (CBZ, 120 mg/kg) and valproic acid (VPA, 400 mg/kg) were randomly sorted in the remaining sessions. The dosage for PTZ, PB and CBZ administration were previously defined for the current experiments (Bachiega et al, 2008), whereas the dose of VPA was based on previous experience with rat (Blanco et al, 2009). The time interval between each AED injection and PTZ administration reflected differences in pharmacokinetics of each different AED: 20 min for CBZ and 30 min for VPA (Lemos and Cavalheiro, 1995;Patsalos, 2005), PB and saline.…”

“…However, the unpredictable nature and variable profile of SRSs in post-SE models make it inadequate, expensive and time-consuming for the testing of new potential AEDs. One strategy to overcome this limitation is to acutely evoke seizures (using PTZ) in rats made epileptic with pilocarpine (Blanco et al, 2009). However, a caveat of this rodent model is the extensive injury, encompassing hippocampus, entorhinal and piriform cortices, amygdala, thalamic and hypothalamic nuclei, claustrum and bed nucleus of stria terminalis (Covolan et al, 2000;Mello et al, 1993).…”

Not all that glitters is gold: A guide to critical appraisal of animal drug trials in epilepsy

“…In addition, the efficacy of a drug may change depending on when it is administered (prior to a seizure, immediately after a brief seizure, or after established status epilepticus),34, 35, 36 and can be altered by multiple factors including vehicle, species, age and sex factors, brain permeability, and pharmacokinetics. Drug effects in disease‐naive conditions may be very different from those during an established disease process, due to changes in the expression or function of key drug targets during the course of a disease 37, 38, 39, 40, 41, 42, 43. Testing a drug with clinically relevant vehicles, testing for target relevance of engagement, using more than one model of seizures including a relevant model of epilepsy or targeted disease or models with different induction methods, and testing across species, ages, and in both sexes may abrogate some of these issues.…”