A role for leukocyte-endothelial adhesion mechanisms in epilepsy

Paolo F. Fabene, Graciela Navarro Mora, Marianna Martinello, Barbara Rossi, Flavia Merigo, Linda Ottoboni, Simona Bach, Stefano Angiari, Donatella Benati, Asmaa Chakir, Lara Zanetti, Federica Schio, Antonio Osculati, Pasquina Marzola, Elena Nicolato, Jonathon W. Homeister, Lijun Xia, John B. Lowe, Rodger P. McEver, Francesco OsculatiAndrea Sbarbati, Eugene C. Butcher, Gabriela Constantin

Research output: Contribution to journalArticlepeer-review

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 α4β1 and αLβ2. 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.

Original languageEnglish
Pages (from-to)1377-1383
Number of pages7
JournalNature Medicine
Volume14
Issue number12
DOIs
Publication statusPublished - Dec 2008

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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