Abstracts

Rationale: While a role for the blood-brain barrier (BBB) in seizures has been accepted, only recently an unexpected contribution of circulating immune cells to the development of acute seizures has been demonstrated in animal models. Endothelial-leukocyte interactions have been shown to contribute to pilocarpine-induced epileptogenesis, and anti-inflammatory regimens aimed at reducing adhesion of white blood cells to the vascular wall prevented status epilepticus (SE; Nat.Med. 14, 1377-1383 (2008); Neurobiol.Dis. 33, 171-271 (2009)). In particular, CD8+ natural killer T cells appear to be involved 1 Since the spleen is a chief regulator of leukocyte activation, and in particular CD8+ mobilization, we wished to test the hypothesis that splenectomy prevents pilocarpine-induced SE. Since cholinergic and glutamatergic receptors are expressed on B- and T-cells (J.Immunol. 170, 4362-4372 (2003); J.Neuroimmunol. 194, 83-88 (2008)), kainic acid and pilocarpine were used as SE inducers. Methods: Rats were monitored for EEG and behavioral changes throughout the experiments. Splenectomy was performed either before (>4 hrs.) or after (3 hrs.) exposure to pilocarpine (350 mg/kg) or kainate acid (10 or 15 mg/kg). Immunocytochemical analysis was used to measure CD3+ cells in spleen. Seizures were quantified by joint time frequency analysis.Results: After SE, spleen displayed a great increase of CD3+ cells regardless of the trigger used to induce seizures. Splenectomy prevented seizure development in all pilocarpine-treated rats (n=9 per group). Low dose kainate caused behavioral modifications that were entirely prevented by splenectomy (n=3). At the convulsive dosage, KA seizures were decreased but not entirely abolished in splenectomized rats (n=4). Splenectomy also prevented SE-induced mortality.Conclusions: Our results show for the first time that splenectomy prevents SE (pilocarpine) or decreases seizure burden (KA) in animal models of acute seizures based on chemical activation of glutamatergic or muscarinic receptors. We hypothesize that white blood cell activation by kainate or pilocarpine may be responsible for blood-brain barrier disruption that precedes seizures.