Letter abstract


Nature Medicine 14, 1377 - 1383 (2008)
Published online: 23 November 2008 | doi:10.1038/nm.1878

A role for leukocyte-endothelial adhesion mechanisms in epilepsy

Paolo F Fabene1, Graciela Navarro Mora1, Marianna Martinello2, Barbara Rossi2, Flavia Merigo1, Linda Ottoboni2, Simona Bach2, Stefano Angiari2, Donatella Benati1, Asmaa Chakir1, Lara Zanetti1, Federica Schio1, Antonio Osculati3, Pasquina Marzola4, Elena Nicolato1, Jonathon W Homeister5, Lijun Xia6, John B Lowe7, Rodger P McEver6, Francesco Osculati1,8, Andrea Sbarbati1, Eugene C Butcher9,10 & Gabriela Constantin2

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The mechanisms involved in the pathogenesis of epilepsy, a chronic neurological disorder that affects approximately one percent of the world population, are not well understood1, 2, 3. 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 alpha4beta1 and alphaLbeta2. 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.

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  1. Department of Morphological-Biomedical Sciences, Section of Anatomy, Strada le Grazie 8, 37134 Verona, Italy.
  2. Department of Pathology, Section of General Pathology, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
  3. Department of Medicine and Public Health, Section of Forensic Medicine, University of Insubria, Via Rossi 9, 21100 Varese, Italy.
  4. Experimental Magnetic Resonance Imaging Center, Faculty of Medicine, University of Verona, Strada le Grazie 8, 37134 Verona, Italy.
  5. University of Carolina at Chapel Hill, Department of Pathology, 420 Brinkhous-Bullitt Building, CB 7525, NC 27599-7525 Chapel Hill, North Carolina 27599-7525, USA.
  6. Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, 825 Northeast Thirteenth Street, Oklahoma City, Oklahoma 73104, USA.
  7. Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA.
  8. Istituto di Ricovero e Cura a Carattere Scientifico Centro Neurolesi Bonino-Pulejo, Via Provinciale Palermo, 98124 Messina, Italy.
  9. Department of Pathology, Stanford University School of Medicine, Stanford, California 94305-5324, USA.
  10. Palo Alto VA Health Care System, 3801 Miranda Avenue, Palo Alto, California 94305, USA.

Correspondence to: Paolo F Fabene1 e-mail: paolo.fabene@univr.it

Correspondence to: Gabriela Constantin2 e-mail: gabriela.constantin@univr.it



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