Abstracts

The li-pilo model reproduces the main features of human temporal lobe epilepsy. After status epilepticus (SE), rats exhibit a latent seizure-free phase followed by a chronic phase during which spontaneous recurrent seizures (SRS) occur. Extensive damage is present in hippocampus, thalamus, amygdala and ventral cortices. The neuroprotective and antiepileptogenic effects of a new drug, RWJ 333369 (RWJ), were investigated in this model. Adult Sprague-Dawley male rats were subjected to SE by injection of LiCl (3 meq/kg) followed 20 h later by pilo (25 mg/kg). RWJ (30, 60, 90 or 120 mg/kg) was injected i.p. at 1 h and 8 h after the onset of SE. Injections were repeated twice a day for 6 days. Another group of rats received diazepam (DZP, 2.5 then 1.25 mg/kg) at 1 h and 8 h of SE. Neuronal damage was assessed 14 days after SE by cell counting on thionine-stained sections. A separate group of rats was video-recorded for 10 h per day to determine the occurrence of the first SRS and the frequency of SRS over four weeks. In DZP-treated rats, the number of neurons was reduced in hippocampus, ventral cortices, medial and lateral thalamus, basolateral and medial amygdala. At all doses, RWJ protected neurons in CA1, dorsolateral part of lateral thalamus and basolateral amygdala. At 60 mg/kg, significant neuroprotection was observed also in anterior part of medial amygdala and layer II of piriform cortex. At 90 and 120 mg/kg, RWJ further afforded marked neuroprotection in posterior part of medial amygdala, ventrolateral part of lateral thalamus, mediodorsal thalamus and deep layers of piriform and ventral entorhinal cortices. Rats exposed to DZP and 30 mg/kg RWJ developed SRS with a similar latency (12-15 days). At 60 mg/kg RWJ, 7 rats developed SRS also after 15 days while 3 developed SRS after a much longer delay (77 days). At the two higher doses, a group of rats developed SRS with a latency similar to DZP-treated rats (90 mg/kg: 15 days, n=4; 120 mg/kg: 13 days, n= 1); a second group developed SRS after a much longer delay (90 mg/kg: 52 days, n=2; 120 mg/kg: 85 days, n=4), and a third group showed no SRS after 5 months (90 mg/kg: n=5; 120 mg/kg: n=4). SRS frequency was reduced by the three higher doses of RWJ and inversely correlated to the latency. RWJ displayed neuroprotective properties in CA1 area of the hippocampus, thalamus, amygdala and ventral cortices. The two higher doses of RWJ that afforded extensive neuroprotection delayed dramatically or prevented the occurrence of SRS. Moreover, when occurrence of SRS was delayed, frequency of SRS was reduced. This suggests that thalamus, amygdala and ventral cortices are involved in circuit reorganizations leading to epilepsy. These results represent the first report of a drug with antiepileptogenic properties in this model of epilepsy. (Supported by Johnson [amp] Johnson Pharmaceutical Research [amp] Development, LLC.)