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

Abstract

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

Frontline Sodium Channel-Blocking Antiseizure Medicine Use Promotes Future Onset of Drug-Resistant Chronic Seizures

“…Furthermore, we presently reveal stark differences in neuroinflammation and neurogenesis between mice exposed to anticonvulsant doses of LTG versus LCM during kindling, suggesting that ASM monotherapy during kindling can dramatically alter the resulting neuropathology in a chronic seizure model. These findings extend our earlier work to indicate that exposure of mice to LTG during corneal kindling induces a state of subsequent pharmacoresistance [8], which closely aligns with findings following chronic administration of LTG to either an amygdala-kindled rat [10,11] or pentylenetetrazol kindled mouse [27]. Importantly, we now demonstrate that there is a significant loss of potency with the ASMs VPA, PB, and PER, or an altogether loss of anticonvulsant efficacy with mechanistically related agents (in the case of CBZ).…”