title: Low potency and limited efficacy of antiepileptic drugs in the mouse 6 Hz corneal kindling model.
abstract: Corneal kindling is a useful alternative to electrically induced amygdala or hippocampal kindling, which requires advanced surgical and EEG techniques that may not be easily available in many laboratories. Therefore the first aim of this study was to evaluate whether repeated 6 Hz corneal stimulation in mice would lead to an increased and persistent seizure response as described for higher frequency (50/60 Hz) corneal kindling. Male NMRI mice stimulated twice daily (except weekends) for 3 s with 6 Hz electrical current at 44 mA displayed robust kindling development, i.e., a progressive increase in seizure severity. The majority of the animals (about 90%) developed a fully kindled state, defined as at least 10 consecutive stage 3-5 seizures within 5 weeks of corneal stimulation. Afterwards, the fully kindled state was maintained for at least 8 weeks with only two days of stimulations per week. Next, the protective efficacy of four mechanistically different antiepileptic drugs (AEDs; clonazepam, valproate, carbamazepine and levetiracetam) was assessed and compared between 6 Hz and 50 Hz fully kindled mice. All tested AEDs showed a relatively lower potency in the 6 Hz kindling model and a limited efficacy against partial seizures was observed with carbamazepine and levetiracetam. We can conclude that 6 Hz kindling may be more advantageous than the previously described 50/60 Hz corneal kindling models due to its robustness and persistence of the fully kindled state. Furthermore, the observed low potency and limited efficacy of AEDs in 6 Hz fully kindled mice suggest that this model could be a useful tool in the discovery of novel AEDs targeting treatment resistant epilepsy.
authors.affiliation: Neuroscience TA, UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Leclercq
authors.affiliation: Neuroscience TA, UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Matagne
authors.affiliation: Neuroscience TA, UCB Pharma, Braine-l'Alleud, Belgium. Electronic address: Rafal.Kaminski@ucb.com.
authors.forename: R M
authors.initials: RM
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D003315:Cornea / Q000503:physiopathology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D007696:Kindling, Neurologic / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D012640:Seizures / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology
chemical_list: D000927:Anticonvulsants
keywords: 6Hz; Epilepsy; Kindling; Levetiracetam; Pharmacoresistance; Seizures