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Genetic background of mice strongly influences treatment resistance in the 6 Hz seizure model
Author(s) -
Leclercq Karine,
Kaminski Rafal M.
Publication year - 2015
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12893
Subject(s) - phenytoin , levetiracetam , potency , anticonvulsant , epilepsy , pharmacology , pharmacokinetics , stimulation , ratón , medicine , chemistry , biochemistry , psychiatry , in vitro
Summary Objective The 6 Hz model of focal seizures has been increasingly used to identify anticonvulsant compounds with potential activity against therapy‐resistant epilepsy, but the protective response to anticonvulsants in this model could be dependent on experimental conditions and selection of mouse strains. Methods Seizure thresholds in the 6 Hz model were compared in CF ‐1, NMRI , and C 57 B l/6 J male mice with two different electrical stimulators (Ugo Basile 5780 and Grass S48). Dose–response curves for phenytoin and levetiracetam were generated in the three strains at 32 and 44 mA current intensities using both devices. Plasma and brain exposure to the two drugs were measured in all three strains. Results CF ‐1 mice had the lowest seizure threshold and responded to phenytoin at 32 mA stimulation intensity, but not at 44 mA. NMRI and C 57 B l/6 J mice had nearly identical threshold values, but NMRI mice responded well to phenytoin at 32 mA and showed limited responsiveness to this drug at 44 mA, whereas C 57 B l/6 J mice were nearly completely resistant to phenytoin. Furthermore, levetiracetam showed limited efficacy and low potency in CF ‐1 and C 57 B l/6 J mice, particularly at 44 mA, whereas in NMRI mice the drug showed much higher potency in all experimental conditions. No obvious difference in the pharmacokinetics of both phenytoin and levetiracetam was detected between the mouse strains that would have explained these unexpected variations in potency. We have also found that the protective effects of both drugs may be influenced by the device type. Significance Collectively these observations clearly indicate that treatment resistance of 6 Hz seizures should be interpreted with strain and experimental conditions in mind. Furthermore, it is important to note that strain differences, much like human genetic differences, may explain why some mice and patients respond to a given treatment and others do not.