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‐pentylene...

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Bibliographic Details
Published in:Animal models and experimental medicine 2020-09, Vol.3 (3), p.245-255
Main Authors: Kumar, Sandeep, Goel, Rajesh K.
Format: Article
Language:English
Subjects:
Albinism
animal models
Bioavailability
Blood-brain barrier
Carbamazepine
Cerebral cortex
Convulsions & seizures
Cornea
Drug dosages
Drug resistance
Drug screening
drug‐resistant epilepsy
Epilepsy
Etiracetam
Gabapentin
Hippocampus
Kindling
Lamotrigine
Methylcellulose
Monoamines
Original
Pentylenetetrazole
Pharmacodynamics
Pharmacokinetics
Phenytoin
refractory epilepsy
Taurine
Topiramate
Zonisamide
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Summary: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 
ISSN:2576-2095
2096-5451
2576-2095
DOI:10.1002/ame2.12131