Corneal kindling in mice: behavioral and pharmacological differences to conventional kindling.
Electrical kindling via unilateral implanted depth electrodes in rats is currently the most commonly used model for temporal lobe epilepsy, but the use of this model in drug screening for the identification of novel anticonvulsants is markedly hampered by the laborious and time-consuming preparation and the size of the animals. Kindling of male mice via transcorneal electrical stimulation has recently proposed as a cost-effective screening model that may improve the preclinical evaluation of efficacy and adverse effect potential of drug candidates for treatment of partial epilepsy. In the present study, corneal kindling was characterized and compared in male and female mice. In fully kindled mice, the anticonvulsant efficacy of the standard antiepileptic drug phenytoin was determined. Large groups of kindled mice were used to examine whether phenytoin non-responders can be selected in the corneal kindling model as reported previously for amygdala kindling. Furthermore, in view of the enhanced adverse effect potential of NMDA antagonists in amygdala kindled rats, it was evaluated whether corneally kindled mice also differ in this respect from non-kindled animals. Mice of both genders could be kindled by twice daily transcorneal stimulation within 10-12 days. However, in contrast to traditional kindling, corneal kindling was associated with a high frequency of mortality, and persistence of the fully kindled state after 4 weeks without stimulation was not pronounced. Phenytoin proved highly potent and efficacious to block corneally kindled seizures. Only one non-responder could be selected out of 75 fully kindled mice repeatedly tested with phenytoin. At 6 days after the last kindled seizure, kindled mice were more sensitive than non-kindled mice to phencyclidine-like behavioral adverse effects of the competitive NMDA antagonist D-CPPene, but this altered sensitivity was not long-lasting, having almost disappeared 27 days after the last seizure, indicating that, in contrast to traditional kindling, brain alterations after corneal kindling are not permanent. In summary, although corneal kindling may have advantages for the identification of new drugs during initial screening of large numbers of compounds, it cannot replace traditional electrical kindling during later phases of drug development. Furthermore, the high mortality and insufficient persistence of corneal kindling in mice detract from the use of this model for repeated drug testing in the same group of animals.
Potschka
H
H
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Löscher
W
W
D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology*; D001259:Ataxia / Q000139:chemically induced / Q000523:psychology; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D003315:Cornea / Q000187:drug effects / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D007696:Kindling, Neurologic / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D010622:Phencyclidine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D012727:Sex Characteristics; D013239:Stereotyped Behavior / Q000187:drug effects; D013997:Time Factors
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; C065286:SDZ EAA 494; D010622:Phencyclidine