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 1 percent of the world population, are not well understood [1][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) and leukocyte integrins α4β1 and αLβ2. Inhibition of leukocytevascular interactions either with blocking antibodies, or in mice genetically deficient in functional PSGL-1, dramatically reduced seizures. Treatment with blocking antibodies following 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 potential leukocyte involvement in the human, leukocytes were more abundant in brains of epileptics than of controls. Our results Correspondence should be addressed to: P.F.F (E-mail: paolo.fabene@univr.it) or G.C. (E-mail: gabriela.constantin@univr.it). Author contribution G.N.M., D.B., A.C., L.Z., F.S. performed epilepsy experiments, telemetry and open field behavior. M.M., B.R., L.O., S.B., S.A., performed intravital microscopy, in vivo staining for adhesion molecules, adhesion assays and contributed to the obtainment of behavioral data. A.O. provided the human samples. F.M., A.C. and F.O. performed immunohistochemistry on human and animal samples. P.M., E.N. and A.S provided MRI expertise. J.W.H., L.X., J.B.L., R.P.M provided vital reagents and mice. E.C.B contributed experimental suggestions, reagents and assistance with writing. P.F.F and G.C. designed the study, analyzed the data and wrote the paper NIH Public Access suggest leukocyte-endothelial interaction as a potential target for the prevention and treatment of epilepsy.Experimental data from animal models as well as human evidence indicate that seizures can lead to neuronal damage and cognitive impairement 2, 3 . However, the molecular mechanisms leading to seizures and epilepsy are not well understood. Recent data suggests that inflammation may play a role in the pathogenesis of epilepsy 4, 5 . For instance, elevation in inflammatory cytokines are seen in the central nervous system (CNS) and plasma in experimental models of seizures and in clinical cases of epilepsy 4, 5 . Moreover, CNS inflammation is associated with breakdown in the blood-brain barrier (BBB), and BBB leakage has been implicated both in the induction of seizures and in the progression to epilepsy 6-9 . Leukocyte recruitment is a hallmark of and a point of therapeutic intervention in tissue inflammation 10,11 , but a role for leukocyte-endothelia...

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

“…4C and D). Taken together, these results suggest that neutrophils could be involved in the development of epilepsy, but not in the induction of acute seizures during viral encephalitis (16,41,43).…”

“…Various cell types of the innate immune system have been hypothesized to be involved in the induction of seizures, including monocytes and neutrophils (41). Mononuclear cell infiltration in epilepsy has been described in mesial temporal lobe epilepsy (TLE) patients; based on the pan-mononuclear cell marker anti-CD45 antibody, a higher number of mononuclear cells (CD45 ϩ ) were observed in the hippocampus of mesial TLE patients compared to control non-mesial TLE stained tissue sections (42,43).…”

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

“…These effects could be mediated by specific leukocyte integrins, such as α4β1 integrin [very late antigen-4 (VLA-4)]. Remarkably, inhibition of leukocyte-vascular interactions with blocking antibodies markedly reduced seizures in this animal model, but, more importantly, treatment with blocking antibodies after SE prevented the development of epilepsy [78]. Interestingly, there is evidence that leukocyte infiltration into the brain is more abundant in individuals with epilepsy than in controls [78].…”

“…Experimental data from a mouse model of TLE indicate that seizures cause increased expression of vascular cell adhesion molecules, and enhance leukocyte rolling and arrest in brain vessels [78]. These effects could be mediated by specific leukocyte integrins, such as α4β1 integrin [very late antigen-4 (VLA-4)].…”

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

“…The rolling and arresting of the leukocyte were successfully suppressed by antibody blockade of VCAM-1 or SELP and by blockade of their respective leukocyte receptors-integrin α4 subunit of the VLA-4 receptor and SELP ligand, respectively. In addition to decreasing spontaneous seizure frequency and duration, the treatment of α4 integrin–specific antibodies also attenuated cortical and hippocampal cell loss [93, 94]. These findings indicate that seizure activity is associated with leukocytic inflammatory changes in the CNS vasculature.…”