A role for leukocyte-endothelial adhesion mechanisms in epilepsy

The present project represents an experimental study on the leukocyte recruitment in the induction and evolution of epilepsy. The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the general world population, are not well understood1-3, but recent data suggest that inflammation may play a role in the pathogenesis of this disease. Leukocyte recruitment is a hallmark of and a point of therapeutic intervention in tissue inflammation, but a role for leukocyte-endothelial interactions in seizure pathogenesis has not been explored. Using a mouse model of epilepsy, pilocarpine induced, we show that seizures induce elevated expression of vascular cell adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and selectins on brain vessels. Intravital microscopy revealed enhanced granulocyte and TH1 lymphocyte interactions (rolling and arrest) in vivo with brain microvasculature after seizures, and these leukocyte-vascular interactions were mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1) and leukocyte integrins α4β1 and αLβ2. Treatment of mice with blocking antibodies dramatically reduced acute and chronic seizures induced by pilocarpine. Genetic deficiency of PSGL-1 or of the α1-3-fucosyltransferases, enzymes involved in the glycosylation of PSGL-1, also inhibited seizures. To further confirm a role for leucocytes in the induction of seizures we performed granulocytes depletion in mice before pilocarpine administration and we again observed a consistent reduction of acute and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability as shown in different recent articles, was induced by acute seizure activity, but it was drastically reduced in anti-α4 treated or PSGL-1 or FucT deficient animals, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. Finally, we provide data suggesting that epilepsy may be correlated in mice with elevated brain leukocyte counts after seizures. Consistent with the potential leukocyte involvement in epilepsy in humans, leukocytes were more abundant in brains of individuals with epilepsy than in controls. Our results suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.