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

Abstract

a b s t r a c tThe efficiency of most of the new antiepileptic drugs (AEDs) on clinical trials still falls short the success reported in pre-clinical studies, possibly because the validity of the animal models is insufficient to fully represent the human pathology. To improve the translational value for testing AEDs, we propose the use of non-human primates. Here, we suggest that triggering limbic seizures with low doses of PTZ in pilocarpine-treated marmosets might provide a more effective basis for the development of AED. Marmosets with epileptic background were more susceptible to seizures induced by PTZ, which were at least 3 times longer and more severe (about 6 times greater frequency of generalized seizures) in comparison to naïve peers. Accordingly, PTZ-induced seizures were remarkably less attenuated by AEDs in epileptic than naïve marmosets. While phenobarbital (40 mg/kg) virtually abolished seizures regardless of the animal's background, carbamazepine (120 mg/kg) and valproic acid (400 mg/kg) could not prevent PTZinduced seizures in epileptic animals with the same efficiency as observed in naïve peers. VPA was less effective regarding the duration of individual seizures in epileptic animals, as assessed in ECoG (p = 0.05). Similarly following CBZ treatment, the behavioral manifestation of generalized seizures lasted longer in epileptic (p < 0.05), which were also more frequent than in the naïve group (p < 0.05). As expected, epileptic marmosets experiencing stronger seizures showed more NPY-and FosB-immunostained neurons in a number of brain areas associated with the generation and spread of limbic seizures. Our results suggest that PTZ induced seizures over an already existing epileptic background constitutes a reliable and controllable mean for the screening of new AEDs.

α-Lipoic acid alleviates pentetrazol-induced neurological deficits and behavioral dysfunction in rats with seizures via an Nrf2 pathway

“…Pentetrazol results in epileptic seizures and the pentetrazol model is one of the most widely used models to assess epilepsy pathogenesis and therapeutic interventions. 29,30 In our research, the pentetrazol-induced model was used to investigate the pathology of epilepsy caused by neuronal apoptosis in the hippocampus area. Researches have shown that seizures lead to signicant increase of reactive oxygen species.…”

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.…”

“…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. Clinical scenarios that could fit this study design of drug preadministration include the prevention of possible seizures in the setting of well-recognized insults, for example, anticipated exposure to toxic agents.…”

The role of the basal ganglia in the control of seizure

“…On the other hand, acute models such as PTZ and MES do not induce SRS and have been indicated to be poor models for AED testing (Loscher 2002). In NHP, pilocarpine (Pontes et al 2016), alumina gel (Mayanagi and Walker 1974; Mayanagi and Walker 1975; Ribak et al 1998), penicillin (Mayanagi and Walker 1975), kainic acid (Chen et al 2014; Yang et al 2015), and electrical kindling (Cleeren et al 2016; Wada and Osawa 1976) have been used to induce TLE. Out of the previously listed methods, only NHP treated with intrahippocampal kainic acid had a change in the hippocampal neuronal volume and developed a partial SRS (Chen et al 2014).…”