Lamotrigine‐resistant corneal‐kindled mice: A model of pharmacoresistant partial epilepsy for moderate‐throughput drug discovery

Koneval, Zachery; Knox, Kevin M.; White, H. Steve; Barker‐Haliski, Melissa

doi:10.1111/epi.14190

Cited by 38 publications

(72 citation statements)

References 38 publications

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“…Limitations in the drug screening program have not been resolved to any significant extent by the recent introduction of a new animal model of drug-resistant epilepsy, although alternate strategies based on modifications of the kindling paradigm has been developed. [7][8][9] These reports and our results ( Figure 2) indicate that the presence of lamotrigine does not hamper kindling development at low doses in mice. Lamotrigine is a second-generation anticonvulsant that produces inhibitory action by reducing the release of the excitatory neurotransmitter glutamate through inhibition of voltage-gated calcium channels 37 and sodium channels.…”

Section: Discussionsupporting

confidence: 74%

“…According to epilepsy benchmarks Area-III (NINDS), the development of new approaches can be advanced by better animal model. 6 To date, three variants of lamotrigine kindling model have shown resistance to antiseizure drugs: (a) lamotrigine-amygdale kindling in rats (electric stimulation) 7 ; (b) lamotrigine-corneal kindling in mice (electric stimulation) 8 ; and (c) lamotrigine-pentylenetetrazole kindling in mice (chemoconvulsant administration). 9 The lamotrigine amygdale kindling model was first described by Postma et al in 2000 and soon after it was adopted by the ETSP.…”

Section: Introductionmentioning

confidence: 99%

“…The pharmacological profile of lamotrigine-corneal kindling model has been recently published. 8 However, drug resistance profile and its underlying mechanism of lamotrigine-pentylenetetrazole kindling model are largely unknown. According to this model, the presence of lamotrigine, at a very low dose, does not hamper pentylenetetrazole kindling in mice; rather, it modifies this epileptogenesis process into drug-resistant epilepsy.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic, pharmacodynamic, and neurochemical investigations of lamotrigine‐pentylenetetrazole kindled mice to ascertain it as a reliable model for clinical drug‐resistant epilepsy

Kumar

Goel

2020

Anim Models and Exp Med

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Background: Pentylenetetrazole kindling has long been used for the screening of investigational antiseizure drugs. The presence of lamotrigine, at a very low dose, does not hamper kindling in mice; rather it modifies this epileptogenesis process into drug-resistant epilepsy. The lamotrigine-pentylenetetrazole kindled mice show resistance to lamotrigine, phenytoin, and carbamazepine. It may also be possible that other licensed antiseizure drugs, like the mentioned drugs, remain ineffective in this model; therefore, this was the subject of this study. Methods: Swiss albino mice were kindled with pentylenetetrazole for 35 days in the presence of either methylcellulose vehicle or lamotrigine (subtherapeutic dose, ie, 5 mg/kg). Vehicle vs lamotrigine-kindled mice were compared in terms of (a) resistance/response toward nine antiseizure drugs applied as monotherapies and two drug combinations; (b) lamotrigine bioavailability in blood and brain; (c) blood-brain barrier integrity; and (d) amino acids and monoamines in the cerebral cortex and hippocampus. Results: Lamotrigine vs vehicle-kindled mice are similar (or not significantly different P > .05 from each other) in terms of (a) response toward drug combinations; (b) lamotrigine bioavailability; and (c) blood-brain barrier integrity except for, significantly (P < .05) reduced taurine and increased glutamate in the cerebral cortex and hippocampus. Aside from these, lamotrigine-kindled mice show significant (P < .05) resistant to lamotrigine (15 mg/kg), levetiracetam (40 mg/kg); carbamazepine (40 mg/kg), zonisamide (100 mg/kg), gabapentin (224 mg/kg), pregabalin (30 mg/kg), phenytoin (35 mg/kg), and topiramate (300 mg/kg). Conclusion: Lamotrigine-pentylenetetrazole kindling takes longer to develop (~5 weeks) in comparison to lamotrigine-amygdale (~4 weeks) and lamotriginecorneal (~2 weeks) kindling models. However, drug screening through this model may yield superior drugs with novel antiseizure mechanisms. How to cite this article: Kumar S, Goel RK. Pharmacokinetic, pharmacodynamic, and neurochemical investigations of lamotrigine-pentylenetetrazole kindled mice to ascertain it as a reliable model for clinical drug-resistant epilepsy. Anim

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic, pharmacodynamic, and neurochemical investigations of lamotrigine‐pentylenetetrazole kindled mice to ascertain it as a reliable model for clinical drug‐resistant epilepsy

Kumar

Goel

2020

Anim Models and Exp Med

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“…In addition to presenting behavioral T A B L E 1 (Continued) seizure and afterdischarge duration data on ASD prototypes, this report also describes noteworthy differences in tolerability between drug-and seizure-experienced animals (ie, lamotrigine-resistant, fully kindled) and TD 50 values obtained in young adult, seizure-and drug-naïve rats. 31 It may also be the case that some sodium channel blockers are more likely to induce resistance, as it has been observed in phenobarbital-resistant kindled rats that are also resistant to phenytoin. The sodium channel blockers (carbamazepine, eslicarbazepine, lacosamide, lamotrigine, phenytoin, and rufinamide) were generally not efficacious in this model and were associated with untoward effects at the highest doses tested.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

et al. 2019

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Objective The lamotrigine‐resistant amygdala kindling model uses repeated administration of a low dose of lamotrigine during the kindling process to produce resistance to lamotrigine, which also extends to some other antiseizure drugs (ASDs). This model of pharmacoresistant epilepsy has been incorporated into the testing scheme utilized by the Epilepsy Therapy Screening Program (ETSP). Although some ASDs have been evaluated in this model, a comprehensive evaluation of ASD prototypes has not been reported. Methods Following depth electrode implantation and recovery, rats were exposed to lamotrigine (5 mg/kg, i.p.) prior to each stimulation during the kindling development process (~3 weeks). A test dose of lamotrigine was used to confirm that fully kindled rats were lamotrigine‐resistant. Efficacy (unambiguous protection against electrically elicited convulsive seizures) was defined as a Racine score < 3 in the absence of overt compound‐induced side effects. Various ASDs, comprising several mechanistic classes, were administered to fully kindled, lamotrigine‐resistant rats. Where possible, multiple doses of each drug were administered in order to obtain median effective dose (ED 50 ) values. Results Five sodium channel blockers tested (eslicarbazepine, lacosamide, lamotrigine, phenytoin, and rufinamide) were either not efficacious or effective only at doses that were not well‐tolerated in this model. In contrast, compounds targeting either GABA receptors (clobazam, clonazepam, phenobarbital) or GABA‐uptake proteins (tiagabine) produced dose‐dependent efficacy against convulsive seizures. Compounds acting to modulate Ca 2+ channels show differential activity: Ethosuximide was not effective, whereas gabapentin was moderately efficacious. Ezogabine and valproate were also highly effective, whereas topiramate and levetiracetam were not effective at the doses tested. Significance These results strengthen the conclusion that the lamotrigine‐resistant amygdala kindling model demonstrates pharmacoresistance to certain ASDs, including, but not limited to, sodium channel blockers, and supports the utility of the model for helping to identify compounds with potential efficacy against pharmacoresistant seizures.

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“…In addition to spontaneous seizures, kindled rodents exhibit a number of behavioral comorbidities of epilepsy, 60,63,69-72 a finding consistent with clinical reports that seizures in humans are just one symptom of epilepsy diagnosis. 73 It is important to note that kindled rodents consistently demonstrate increased anxiety-like behaviors and cognitive deficits in a diversity of approaches performed by numerous independent investigators, 60,63,67,68 further supporting the utility of kindling for studies of disease-modification and/or epileptogenesis and demonstrating that these behavioral comorbidities are relevant biomarkers in kindling models, as well as models with spontaneous recurrent seizures (SRS). Kindled models offer the capability to tightly control the epileptogenesis process in a manner that is distinct from other models of epilepsy.…”

Section: Background Of Kindling For Antiepileptogenesis/disease Modifmentioning

confidence: 94%

A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force

et al. 2018

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SummaryPreclinical pharmacology studies in animal models of seizures and epilepsy have provided a platform to identify more than 20 antiseizure drugs in recent decades. To minimize variability in lab‐to‐lab studies and to harmonize approaches to data collection and reporting methodology in pharmacologic evaluations of the next generation of therapies, we present common data elements (CDEs), case report forms (CRFs), and this companion manuscript to help with the implementation of methods for studies in established preclinical seizure and epilepsy models in adult rodents. The development of and advocacy for CDEs in preclinical research has been encouraged previously by both clinical and preclinical groups. It is anticipated that adoption and implementation of these CDEs in preclinical studies may help standardize approaches to minimize variability and increase the reproducibility of preclinical studies. Moreover, they may provide a methodologic framework for pharmacology studies in atypical animal models or models in development, which may ultimately promote novel therapy development. In the present document, we refer selectively to animal models that have a long history of preclinical use, and in some cases, are clinically validated.

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Lamotrigine‐resistant corneal‐kindled mice: A model of pharmacoresistant partial epilepsy for moderate‐throughput drug discovery

Abstract: The pharmacoresistant LTG-resistant CKM provides an etiologically relevant moderate-throughput platform that is suitable for early compound discovery before advancing to more resource-intensive models of epilepsy.

Cited by 38 publications

References 38 publications

Pharmacokinetic, pharmacodynamic, and neurochemical investigations of lamotrigine‐pentylenetetrazole kindled mice to ascertain it as a reliable model for clinical drug‐resistant epilepsy

Pharmacokinetic, pharmacodynamic, and neurochemical investigations of lamotrigine‐pentylenetetrazole kindled mice to ascertain it as a reliable model for clinical drug‐resistant epilepsy

Evaluation of antiseizure drug efficacy and tolerability in the rat lamotrigine‐resistant amygdala kindling model

A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force

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