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

摘要

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.