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Characterization of a Lamotrigine‐Resistant Kindled Model of Epilepsy in Mice: Evaluation of Drug Resistance Mechanisms
Author(s) -
Singh Ekta,
Pillai Krishna K.,
Mehndiratta ManMohan
Publication year - 2014
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12238
Subject(s) - lamotrigine , anticonvulsant , pharmacology , epilepsy , kindling , valproic acid , carbamazepine , histamine , kindling model , chemistry , medicine , psychiatry
The aims of this study were to characterize a lamotrigine‐resistant kindled model of epilepsy in mice, to study the anticonvulsant effect of carbamazepine ( CBZ ) and valproic acid ( VPA ), and to probe into the mechanism for resistance. Swiss albino mice were kindled by a subconvulsive dose of pentylenetetrazole ( PTZ , 30 mg/kg, i.p., every other day for 6 weeks). The mice were pre‐treated (30 min.) either with a low dose of LTG (5 mg/kg, i.p.) or with vehicle, and the seizures were scored. The acute treatment with LTG (15 mg/kg, i.p.) on the last day blocked seizure in the vehicle‐treated group, but the LTG pre‐treated group showed resistance. This resistance was extended to CBZ , but not to VPA . The resistant model was successfully replicated in mice with less kindling development time (6 weeks versus 9 weeks 5 days in rats). A highly significant decrease in the level of histamine ( p < 0.001) was found, and there were also decreases in serotonin, GABA and AChE levels ( p < 0.05). A significantly low level of histamine correlates with drug resistance and indicates involvement of the H1/H3 receptors. It is suggested that the selective action on voltage‐gated Na + and Ca 2+ channels could explain the differences in the sensitivity of CBZ and VPA .