Rapid kindling in preclinical anti-epileptic drug development: the effect of levetiracetam.
OBJECTIVE
This study assesses the use of the serial day Rapid Kindling with Recurrent Hippocampal Seizures (RKRHS) model in drug testing by investigating the anti-epileptic effect of levetiracetam (LEV), a novel anti-epileptic drug (AED) with a unique preclinical profile.


METHODS
Male Wistar rats (n=16) were implanted with a stimulation/recording electrode unit in the right hippocampus and epidural recording electrodes. One week later, all rats received 12 stimulations each day for several consecutive days according to the serial day RKRHS protocol, until they were fully kindled. Fully kindled rats were then randomly assigned to an active (n=8) and a control (n=6) group and injected once (intraperitoneal, i.p.) with levetiracetam (54 mg/kg) or saline (0.9% NaCl, 2 ml/kg), respectively. One hour later, the rats received additional kindling stimulations, during which the effect of LEV was assessed.


RESULTS
One hour following injection of LEV, mean seizure stage dropped to 1.67+/-1.03 compared to 5+/-0 in controls (p<0.05). Mean ADD was also significantly shorter in the active group than in controls; 21.16+/-5.03 s versus 57.24+/-8.16s, respectively (p<0.05). A gradual, time-dependent decline was noted in the anti-epileptic effect of LEV but this effect stayed statistically significant at least up to 2.5 h (p<0.05).


CONCLUSIONS
LEV was demonstrated to have anti-epileptic properties in RKRHS that compared to those in traditional kindling and contrast with results from classical screening tests. RKRHS may represent a valuable and sensitive screening tool early in the drug screening process.
De Smedt
Tim
T
Reference Center for Refractory Epilepsy, Department of Neurology, Heymans Institute, Second Floor, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. T.DeSmedt@UGent.be
Vonck
Kristl
K
Raedt
Robrecht
R
Dedeurwaerdere
Stefanie
S
Claeys
Pieter
P
Legros
Benjamin
B
Wyckhuys
Tine
T
Wadman
Wytse
W
Boon
Paul
P
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003292:Convulsants; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007696:Kindling, Neurologic / Q000502:physiology*; D000077287:Levetiracetam; D008297:Male; D010433:Pentylenetetrazole; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control
D000927:Anticonvulsants; D003292:Convulsants; D000077287:Levetiracetam; D010433:Pentylenetetrazole; D010889:Piracetam