Abstracts

Rationale: Classic anticonvulsants suppress acute seizures, but not epileptogenesis. The mechanisms of epileptogenesis is likely to be different from that of the epilepsy. One of initiating events (brain insults) for epilepsy can be experimentally reproduced in the model of status epilepticus (SE) induced in mice by pilocarpine (PILO). In the present study, we evaluated the possibility of prophylactic treatment with high dose of Levetiracetam (LEV) by using this model in which epileptogenesis with brain damages develop after SE Methods: Adult male ICR mice were injected with PILO (290 mg/kg, i.p.) 30 min after methyl scopolamine (1.mg/kg, i.p.) treatment. Seizures were terminated by DZP (5 mg/kg, i.p.) injection in the mice displayed five times limbic generalized seizures during 90 min. The occurrence of spontaneous recurrent seizures (SRS) was recorded during and after treatment. The assessments of the brain edema, brain injury and blood-brain-barrier (BBB) failure were performed by MRI (DWI and T2WI as biomarkers) and histological studies using several staining. During 28 days after the end of the SE, LEV (250 and 500 mg/kg, p.o.) were administrated twice a day from 1 hour after SE. Results: SRS occurred at 7 (2~10) days after the DZP injection. LEV continuously treated SE mice did not occur SRS during at least 28 days after the DZP injection. The mortality during 28 days after SE dramatically decreased following treatment with LEV. DWI and T2WI changes were found in the parietal cortex, hippocampus, piriform cortex, and thalamus. Signal intensities in hippocampus and amygdala peaked on Day 2, and returned to basal intensity levels by Day 7. This time course is consistent with cell death and an inflammatory process. DWI demonstrated cytotoxic edema 3h after SE, and day 2 after SE, vasogenic edema related to the breakdown of the BBB could be the predominant DWI and T2WI findings in the epileptogenic area. LEV continuous treatment significantly suppressed signal intensities of these biomarkers in hippocampus and amygdala, and the BBB failure was prevented by LEV treatment in PILO-SE mice. Conclusions: In the model of PILO-SE, the occurrence of SRS after DZP was strongly associated with neuronal degeneration by the early events after SE as brain cytotoxic and vasogenic edema, microglia activation as neuroinflammatory process and BBB failures. DWI and T2WI findings may be variable after SE, dependent on the predominance of cytotoxic and vasogenic edema. These data indicate that the continuous treatment with LEV during at least 2 days (6 times injections) after SE is important for control of neuronal degeneration by the prevention of sequential events. Therefore, these evidence suggest the possibility of prophylactic treatment with high dose LEV which exerts anti-epileptogenic or neuroprotective activity.