Monday July 3, 2006 15:00-17:00 Ballroom 1 Discussion Group Session Blood-brain barrier and epilepsy

Abstract

Abstract 1 D. Janigro ( 1 Cleveland Clinic Foundation, USA ) One of the most commonly used animal model of status epilepticus (SE) is based on the intra peritoneal injection of the cholinergic agonist pilocarpine. While in vivo administration leads to acute SE in approximately the 70% of the cases, in vitro electrophysiological studies have shown that pilocarpine causes epileptogenic activity preferentially when co-applied with other proconvulsants. Moreover, radioactive tracer experiments suggested low brain accumulation of pilocarpine. We measured the potency of pilocarpine when directly applied to hippocampal slices and we compared the in vitro pilocarpine ED50 with the levels measured in the brain after i.p. injection of 350 mg/Kg before (Stage 4) and at SE. Staging of pilocarpine effects were performed by video EEG monitoring. At concentrations up to 500 □M, synchronized epileptiform activity in vitro was never seen. Similar in vitro potency was observed when using a guinea pig whole brain preparation. In contrast, kainic acid induced dramatic electrographic seizures when applied at 4 □M. Surprisingly, pilocarpine brain levels measured after i.p. injection never exceed 60 □M and were on average around 5% of serum levels. We measured blood-brain barrier permeability by 14C-Sucrose, 3H-Diazepam and FITC-albumin to determine if altered BBB function may affect pilocarpine penetration. Before SE, only modest modifications of BBB permeability to FITC-albumin or radiotracers was observed. Pilocarpine permeability was compared to the permeability of sucrose and diazepam to reveal significantly lower permeation than predicted by its lipophilicity. Beside CNS cholinergic effects, significant pro-inflammatory changes (increased serum levels of IL-1□ and changes in the CD4:CD8 T-Cells) were observed after pilocarpine injection and before Stage 4 or SE. Our results show a discrepancy between the in vivo and in vitro pilocarpine proepileptogenic effects and reveal, in vivo, the occurrence of an early peripheral inflammatory event that may cooperate to the establishment of SE.