A role for leukocyte-endothelial adhesion mechanisms in epilepsy.
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.
Fabene
Paolo F
PF
Navarro Mora
Graciela
G
Martinello
Marianna
M
Rossi
Barbara
B
Merigo
Flavia
F
Ottoboni
Linda
L
Bach
Simona
S
Angiari
Stefano
S
Benati
Donatella
D
Chakir
Asmaa
A
Zanetti
Lara
L
Schio
Federica
F
Osculati
Antonio
A
Marzola
Pasquina
P
Nicolato
Elena
E
Homeister
Jonathon W
JW
Xia
Lijun
L
Lowe
John B
JB
McEver
Rodger P
RP
Osculati
Francesco
F
Sbarbati
Andrea
A
Butcher
Eugene C
EC
Constantin
Gabriela
G
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
D015815:Cell Adhesion Molecules