title: A role for leukocyte-endothelial adhesion mechanisms in epilepsy.
abstract: The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood. Using a mouse model of epilepsy, we show that seizures induce elevated expression of vascular cell adhesion molecules and enhanced leukocyte rolling and arrest in brain vessels mediated by the leukocyte mucin P-selectin glycoprotein ligand-1 (PSGL-1, encoded by Selplg) and leukocyte integrins alpha(4)beta(1) and alpha(L)beta(2). Inhibition of leukocyte-vascular interactions, either with blocking antibodies or by genetically interfering with PSGL-1 function in mice, markedly reduced seizures. Treatment with blocking antibodies after acute seizures prevented the development of epilepsy. Neutrophil depletion also inhibited acute seizure induction and chronic spontaneous recurrent seizures. Blood-brain barrier (BBB) leakage, which is known to enhance neuronal excitability, was induced by acute seizure activity but was prevented by blockade of leukocyte-vascular adhesion, suggesting a pathogenetic link between leukocyte-vascular interactions, BBB damage and seizure generation. 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.
authors.forename: Paolo F
authors.initials: PF
authors.lastname: Fabene
authors.forename: Graciela
authors.initials: G
authors.lastname: Navarro Mora
authors.forename: Marianna
authors.initials: M
authors.lastname: Martinello
authors.forename: Barbara
authors.initials: B
authors.lastname: Rossi
authors.forename: Flavia
authors.initials: F
authors.lastname: Merigo
authors.forename: Linda
authors.initials: L
authors.lastname: Ottoboni
authors.forename: Simona
authors.initials: S
authors.lastname: Bach
authors.forename: Stefano
authors.initials: S
authors.lastname: Angiari
authors.forename: Donatella
authors.initials: D
authors.lastname: Benati
authors.forename: Asmaa
authors.initials: A
authors.lastname: Chakir
authors.forename: Lara
authors.initials: L
authors.lastname: Zanetti
authors.forename: Federica
authors.initials: F
authors.lastname: Schio
authors.forename: Antonio
authors.initials: A
authors.lastname: Osculati
authors.forename: Pasquina
authors.initials: P
authors.lastname: Marzola
authors.forename: Elena
authors.initials: E
authors.lastname: Nicolato
authors.forename: Jonathon W
authors.initials: JW
authors.lastname: Homeister
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
authors.forename: John B
authors.initials: JB
authors.lastname: Lowe
authors.forename: Rodger P
authors.initials: RP
authors.lastname: McEver
authors.forename: Francesco
authors.initials: F
authors.lastname: Osculati
authors.forename: Andrea
authors.initials: A
authors.lastname: Sbarbati
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Butcher
authors.forename: Gabriela
authors.initials: G
authors.lastname: Constantin
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004569:Electroencephalography; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D007962:Leukocytes / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D015815:Cell Adhesion Molecules