Abstracts

Rationale: The blood-brain barrier (BBB) and brain inflammation are new targets in epilepsy research and bear significant treatment promise. While inflammation and cerebrovasculature damage have been previously been ascribed to preceding epileptic activity, we recently a novel spatiotemporal pattern of inflammation and BBB damage leading to seizures. In particular, we discovered that a systemic inflammation constitutes an etiological trigger leading to seizures in animal models of temporal lobe epilepsy. This was also shown in previous studies showing that blood-brain barrier disruption causes acute seizures in human subjects. Methods: Adult rats were injected intraperitoneally with the following: 1) LiCl (3meq/Kg); 2) pilocarpine (320 mg/Kg); 3) LiCl (3meq/kg) + pilocarpine (30 mg/Kg); 4) pilocarpine (30 mg/Kg) + LiCl (3 meq/Kg). Video-EEG was performed in all the groups. BBB integrity and serum markers of pro-inflammatory process (IL-1β) were confirmed in correspondence of pre-ictal EEG changes. The effect of IL-1 receptor antagonist (IL-RA, 3’5 -34 μg/Kg) on seizure development was evaluated by video-EEG. Results: EEG recordings revealed a marked 4-5 Hz activity and increased peak amplitude starting 3 hours following LiCl administration. Such EEG changes occurred concurrently with increased IL-1β serum levels and BBB leakage. Pilocarpine (320 mg/kg) triggered identical pro-inflammatory effects prior to status epilepticus (SE). Interestingly, SE was elicit by the combination of LiCl and pilocarpine (30 mg/Kg) irrespective of their sequence of administration. Pre-treatment with intravenous IL-1RA reduced the onset of pilocarpine induced SE (4/13 rats) and increased the overall survival of the animals. Conclusions: Our results demonstrate that an acute intravascular inflammatory process resulting in BBB damage precede the onset of seizures. This was true irrespective of the trigger used (lithium or pilocarpine) or the sequence of administration (in the Li-pilocarpine model). Blockade of the IL-1β system reduced the probability of developing SE. This warrants further studies to evaluate the efficacy of an anti-inflammatory treatment for seizure disorders.