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

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 lamotrigine-corneal (~2 weeks) kindling models. However, drug screening through this model may yield superior drugs with novel antiseizure mechanisms.