Rapid kindling in preclinical anti-epileptic drug development: The effect of levetiracetam

Purpose: 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 (it = 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 stagedropped 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 +/- 8.16 s, 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 (p < 0.05). Conclusion: 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. (c) 2005 Elsevier B.V. All rights reserved.