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 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.

[1]  C. Lowell,et al.  Deficiency of Src family kinases p59/61hck and p58c-fgr results in defective adhesion-dependent neutrophil functions , 1996, The Journal of cell biology.

[2]  Simona Frigerio,et al.  Expression of Adhesion Factors Induced by Epileptiform Activity in the Endothelium of the Isolated Guinea Pig Brain In Vitro , 2007, Epilepsia.

[3]  W. Löscher,et al.  Repeated low-dose treatment of rats with pilocarpine: low mortality but high proportion of rats developing epilepsy , 2001, Epilepsy Research.

[4]  John S Duncan,et al.  Seizure-induced neuronal injury: Human data , 2002, Neurology.

[5]  R. Ransohoff,et al.  Three or more routes for leukocyte migration into the central nervous system , 2003, Nature Reviews Immunology.

[6]  K. Ley,et al.  Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation , 2004, Nature Reviews Immunology.

[7]  P. Rutecki,et al.  Ictal epileptiform activity in the CA3 region of hippocampal slices produced by pilocarpine. , 1998, Journal of neurophysiology.

[8]  D. Margineanu,et al.  Pilocarpine-induced epileptogenesis in the rat: Impact of initial duration of status epilepticus on electrophysiological and neuropathological alterations , 2002, Epilepsy Research.

[9]  E. Oby,et al.  The Blood–Brain Barrier and Epilepsy , 2006, Epilepsia.

[10]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.

[11]  Bret N. Smith,et al.  Pilocarpine-induced status epilepticus results in mossy fiber sprouting and spontaneous seizures in C57BL/6 and CD-1 mice , 2002, Epilepsy Research.

[12]  Richard Dodel,et al.  Cost of epilepsy: a systematic review. , 2008, PharmacoEconomics.

[13]  M. Avoli,et al.  Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro , 2002, Progress in Neurobiology.

[14]  U. V. von Andrian,et al.  The alpha(1,3)fucosyltransferases FucT-IV and FucT-VII exert collaborative control over selectin-dependent leukocyte recruitment and lymphocyte homing. , 2001, Immunity.

[15]  P. Kubes,et al.  The alpha4-integrin: an alternative pathway for neutrophil recruitment? , 1999, Immunology today.

[16]  J. Meno,et al.  Adenosine-induced modulation of excitatory amino acid transport across isolated brain arterioles. , 2003, Journal of neurosurgery.

[17]  V. Perry,et al.  Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral vascular endothelium during neutrophil-induced blood–brain barrier breakdown in vivo , 1998, Neuroscience.

[18]  A. Vezzani,et al.  Brain Inflammation in Epilepsy: Experimental and Clinical Evidence , 2005, Epilepsia.

[19]  R. Cummings,et al.  P-selectin glycoprotein ligand-1-deficient mice have impaired leukocyte tethering to E-selectin under flow. , 2002, The Journal of clinical investigation.

[20]  R. Alon,et al.  Immune cell migration in inflammation: present and future therapeutic targets , 2005, Nature Immunology.

[21]  Alon Friedman,et al.  TGF-beta receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. , 2007, Brain : a journal of neurology.

[22]  W. Löscher,et al.  Behavioral alterations in the pilocarpine model of temporal lobe epilepsy in mice , 2007, Experimental Neurology.

[23]  M. Cybulsky,et al.  Getting to the site of inflammation: the leukocyte adhesion cascade updated , 2007, Nature Reviews Immunology.

[24]  C. Doig,et al.  Functional α4-integrin: A newly identified pathway of neutrophil recruitment in critically ill septic patients , 2001, Nature Medicine.

[25]  L. Piccio,et al.  Chemokines trigger immediate beta2 integrin affinity and mobility changes: differential regulation and roles in lymphocyte arrest under flow. , 2000, Immunity.

[26]  Jens P Dreier,et al.  Lasting Blood-Brain Barrier Disruption Induces Epileptic Focus in the Rat Somatosensory Cortex , 2004, The Journal of Neuroscience.

[27]  E. Aronica,et al.  Blood-brain barrier leakage may lead to progression of temporal lobe epilepsy. , 2007, Brain : a journal of neurology.

[28]  Eugene C. Butcher,et al.  Molecular Mechanisms Involved in Lymphocyte Recruitment in Inflamed Brain Microvessels: Critical Roles for P-Selectin Glycoprotein Ligand-1 and Heterotrimeric Gi-Linked Receptors1 , 2002, The Journal of Immunology.

[29]  Petr Malý,et al.  The α(1,3)Fucosyltransferase Fuc-TVII Controls Leukocyte Trafficking through an Essential Role in L-, E-, and P-selectin Ligand Biosynthesis , 1996, Cell.

[30]  Gregory L. Holmes,et al.  Seizure-induced neuronal injury: Animal data , 2002, Neurology.

[31]  P. Marzola,et al.  Magnetic resonance imaging of changes elicited by status epilepticus in the rat brain: diffusion-weighted and T2-weighted images, regional blood volume maps, and direct correlation with tissue and cell damage , 2003, NeuroImage.

[32]  D. Janigro,et al.  Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy. , 2003, Current drug targets.

[33]  M. Lebwohl,et al.  A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. , 2003, The New England journal of medicine.

[34]  V M Runge,et al.  The use of Gd DTPA as a perfusion agent and marker of blood-brain barrier disruption. , 1985, Magnetic resonance imaging.

[35]  Ludwig Kappos,et al.  A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. , 2006, The New England journal of medicine.

[36]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. 3. Mechanisms. , 1972, Electroencephalography and clinical neurophysiology.

[37]  G. Bernardi,et al.  T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules : a critical role for P-selectin glycoprotein ligand-1 , 2003 .

[38]  Imad Najm,et al.  In Vivo and In Vitro Effects of Pilocarpine: Relevance to Ictogenesis , 2007, Epilepsia.