The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models

Löscher, Wolfgang; Fassbender, C. P.; Nolting, Björn

doi:10.1016/0920-1211(91)90075-q

Cited by 310 publications

(192 citation statements)

References 27 publications

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“…Thus, antiseizure efficacy of ASDs such as CBZ and of other ASDs at high neurotoxic doses as reported by Duveau et al35 in the intrahippocampal kainate mouse model are difficult to interpret. On the basis of previous pharmacokinetic analyses in mice,51 plasma concentrations achieved at time of maximum antiseizure effect of CBZ (15 min) at the doses used in the present study would be 7.3 μg/ml (20 mg/kg) and 14.5 μg/ml (40 mg/kg), which is closely related to the “therapeutic plasma concentration range” (4–12 μg/ml) in patients with epilepsy 52. The pharmacokinetic analyses also showed that, because of rapid elimination, the duration of the antiseizure effect in mice is only about 2 h,51 which was also found in the present experiments.…”

Section: Discussionmentioning

confidence: 99%

The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain

Twele¹,

Töllner²,

Bankstahl³

et al. 2016

Epilepsia Open

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SummaryObjectiveMesial temporal lobe epilepsy (TLE) with hippocampal sclerosis is a predominant form of acquired epilepsy, characterized by recurrent simple and complex partial seizures that are often resistant to treatment. Mice developing spontaneous recurrent nonconvulsive and convulsive seizures after intrahippocampal injection of the excitotoxic glutamate agonist kainate are thought to represent a valuable model of mesial TLE. Epileptic electroencephalogram (EEG) activity recorded in this model from the kainate focus in the ipsilateral hippocampus is resistant to antiseizure drugs such as carbamazepine (CBZ). We compared the efficacy of CBZ in this model in two different mouse strains (FVB/N and NMRI). Furthermore, we evaluated whether changes in the definition of electrographic seizures affect the antiseizure efficacy of CBZ.MethodsAs in previous studies, two types of epileptic EEG activity were defined: high‐voltage sharp waves (HVSWs) and hippocampal paroxysmal discharges (HPDs). The characteristics of these paroxysmal EEG events in epileptic mice were compared with EEG criteria for nonconvulsive seizures in patients. For HVSWs, different spike frequencies, interevent intervals, and amplitudes were used as inclusion and exclusion criteria. In addition to CBZ, some experiments were performed with diazepam (DZP) and phenobarbital (PB).ResultsFemale epileptic FVB/N mice predominantly exhibited frequent HVSWs, but only infrequent HPDs or secondarily generalized convulsive seizures. Slight changes in HVSW definition determined whether they were resistant or responsive to CBZ. Male NMRI mice exhibited both HVSWs and HPDs. HVSWs were more resistant than HPDs to suppression by CBZ. Both types of epileptic EEG activity were rapidly suppressed by DZP and PB.SignificanceThe data demonstrate that focal electrographic seizures in the intrahippocampal kainate mouse model are less resistant than previously thought. Both mouse strain and the criteria chosen for definition of EEG seizures determine whether such seizures are drug‐resistant or ‐responsive.

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Section: Discussionmentioning

confidence: 99%

The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain

Twele¹,

Töllner²,

Bankstahl³

et al. 2016

Epilepsia Open

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“…With the MES and PTZ threshold tests in mice and rats, we previously showed that the use of doses leading to plasma concentrations similar to the therapeutic plasma concentration range known from patients with epilepsy results in clinically predictive data, in that the drugs are effective in rodents in the same plasma concentration range as in humans, although doses (in mg/kg) needed to achieve these drug levels in rodents are generally much higher than respective doses in humans (27,28). However, in contrast to our previous kindling studies (13) and the present experiments, drug testing in the MES and PTZ tests does not allow delineation of interindividual differences in drug response.…”

Section: Discussionmentioning

confidence: 99%

Effects of the Novel Antiepileptic Drug Levetiracetam on Spontaneous Recurrent Seizures in the Rat Pilocarpine Model of Temporal Lobe Epilepsy

et al. 2002

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Summary:Purpose: Animal models in which seizures are elicited by chemical or electrical means are commonly used for identification and preclinical testing of novel antiepileptic drugs (AEDs). Such models have been successful in discovering all the new AEDs. However, despite the high efficacy of AEDs against elicited seizures in rodent models, a significant proportion of epilepsy patients with spontaneous recurrent seizures is resistant to these drugs. It is not known whether drug testing in rodent models with spontaneous recurrent seizures would yield a more predictive result with respect to AED efficacy in the clinic. This led us to test one of the novel AEDs, levetiracetam (LEV), in a rat model of temporal lobe epilepsy (TLE) with spontaneous recurrent seizures.Methods: Wistar rats were subjected to pilocarpine-induced status epilepticus and recorded for spontaneous recurrent seizures in the months after pilocarpine treatment. A group of rats with frequent spontaneous seizures was used for the drug trial with LEV. The experimental protocol for drug testing in these rats was as follows. For 2 weeks, rats received subcutaneous implantation of osmotic minipumps filled with saline (predrug control period), followed by a 2-week period with implantation of LEV-filled minipumps (drug period), after which pumps were replaced by drug-free pumps for 2 weeks (postdrug control period). The LEV concentration in the pumps during the drug period was adjusted to give daily doses resulting in the maximal plasma concentration range determined previously in patients with TLE during prolonged treatment with LEV. During the 6 weeks of the experiment in epileptic rats, seizures were recorded by video monitoring.Results: Average seizure frequency during the pre-and postdrug control period in a group of eight epileptic rats was 21 and 25 seizures. This was reduced to an average seizure frequency of 8 seizures during the 2 weeks of treatment with LEV. However, the individual response of rats to LEV varied markedly from complete seizure control to no effect at all, although plasma drug levels were within the therapeutic range in all rats. When seizure frequency was separately calculated for the first and second week of treatment, the significant anticonvulsant effect determined in the first week was partially diminished in the second week, suggesting that tolerance may have developed in some of the rats.Conclusions: The data demonstrate that interesting results can be obtained by drug testing in epileptic rats, giving a more realistic prediction of clinical efficacy than results from drug testing in animal models with elicited seizures. Thus, although drug trials in rats with spontaneous recurrent seizures are laborious and time-consuming, such trials should be added to the preclinical characterization of novel AEDs.

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“…The MES test is considered to be a predictor of likely therapeutic efficacy against generalized tonic-clonic seizures. Generally, compounds with anticonvulsant activity in petit mal epilepsy are effective in PTZ induced seizure model (Löscher et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant effect of the ethanol extract of Caesalpiniapulcherrima (L.) Sw., Fabaceae, leaves

Kumar¹,

Singh²,

Baghotia³

et al. 2010

Rev. bras. farmacogn.

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ABSTRACT:In this study, ethanol extract of Caesalpinia pulcherrima (L.) Sw., Fabaceae, leaves (CPEE) was investigated for anticonvulsant effect against maximal electroshock (MES) and pentylenetetrazole (PTZ) induced seizures in rats and mice at dose levels 200 and 400 mg/ kg, i.p. respectively. Diazepam (3 mg/kg, i.p.) was used as a standard anticonvulsant drug for comparison. CPEE was found to be safe up to the dose of 4000 mg/kg in mice, when administered intraperitoneally. The extract at 400 mg/kg dose produced significant (p<0.01) anticonvulsant effect w.r.t. control against PTZ-induced clonic seizures. In MES-induced seizure model, there were no significant alterations in the onset as well as duration of hind limb extension seizures as compared to control at a dose of 200 mg/kg when administered intraperitoneally. However, the extract (CPEE, 400 mg/kg i.p.) significantly (p<0.01) delayed the onset as well as decreased the duration of hind limb extension seizures (HLES) as compared to control. However, the extract, CPEE, percentage protection of the animals was increased at higher dose (200 mg/kg) in both the models. The results of the study suggest that ethanol extract of Caesalpinia pulcherrima (L.) Sw. leaves possess anticonvulsant effect.

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The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models

Cited by 310 publications

References 27 publications

The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain

The effects of carbamazepine in the intrahippocampal kainate model of temporal lobe epilepsy depend on seizure definition and mouse strain

Effects of the Novel Antiepileptic Drug Levetiracetam on Spontaneous Recurrent Seizures in the Rat Pilocarpine Model of Temporal Lobe Epilepsy

Anticonvulsant effect of the ethanol extract of Caesalpiniapulcherrima (L.) Sw., Fabaceae, leaves

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