VALIDATION OF CORNEALLY KINDLED MICE - A SENSITIVE SCREENING MODEL FOR PARTIAL EPILEPSY IN MAN

Epileptogenesis induced by electrical kindling of rats appears to be s uperior to the acute maximal electroshock seizure (MES) test in normal animals in predicting the efficacy and adverse effect potential of dr ugs in patients with partial epilepsy. Unfortunately, inclusion of suc h kindling models in primary screening is hampered by the laborious an d expensive procedure of stimulation and recording with implanted brai n electrodes. Furthermore the size of the rats excludes their use in i nitial testing where compound availability is often limited for the 'f irst batch synthesis'. The present study demonstrates that chronic ele ctrical stimulation with corneal electrodes in mice can rapidly yield large numbers of kindled animals with a seizure phenomenology reflecti ng partial seizures in man. A pharmacological characterisation showed that corneally kindled mice can be used repeatedly for several drug ex periments with reproducible results. The seizure protection and advers e effect potential obtained with proven antiepileptic drugs were simil ar to the effects observed in amygdala kindled rats and their correspo nding clinical profile in partial epilepsy. Protection was obtained wi th vigabatrin and levetiracetam in this new model despite their lack o f anticonvulsant activity in the acute MES test. Furthermore, in agree ment with clinical findings with NMDA antagonists, MK-801 revealed mor e severe adverse effects in corneally kindled mice than in normal anim als. These results suggest that corneal kindling of mice represents a sensitive and valid screening model for the identification of new ther apies for partial epilepsy in man. (C) 1998 Elsevier Science B.V. All rights reserved.