Role of neuroinflammation in experimental epilepsy

Major advances in the understanding of basic mechanisms of epilepsy have come through studies of experimental models of temporal lobe epilepsy (TLE); However, several significant disparities between the features of the human disorder and those of the currently used animal models may have been insufficiently considered. In this regard, no effective treatments currently exist to protect the brain from seizure-induced cell death and prevent future development of chronic epilepsy. A new perspective is rising up in the study of epileptogenesis. Modulation of inflammatory reactions in the brain and targeting of inflammatory mediators may be effective therapeutic strategies to prevent or limit epileptogenesis in the vulnerable nervous system, and compounds which specifically interfere with the adhesive docking structure may constitute a new generation of highly specific anti-neuroinflammatory drugs. In the present study, pilocarpine model of TLE has been used to study the role of leukocyte recruitment in epilepsy. A direct effect on endothelial cells has been shown using pilocarpine when inducing epilepsy. Intravital microscopy, determination of blood-brain barrier (BBB) permeability, telemetry EEG, MRI, behavioral assessment and immunohistochemistry are some of the techniques here employed. We first studied endothelial activation and found that acute seizure activity following pilocarpine administration led to enhanced vascular expression of leukocyte adhesion molecules. Results showed that elicited seizure activity was associated with inflammatory changes in the central nervous system (CNS) vasculature. Furthermore, treatment with antibody to 4 integrin and its ligand VCAM-1 after status epilepticus was effective in preventing spontaneous convulsions during the chronic phase, and neutrophil depletion caused a substantial reduction in status epilepticus and spontaneous recurrent convulsions, confirming that leukocytes contribute to seizure pathogenesis. Leukocyte depletion results, strongly support the idea that blockade of leukocyte dependent phenomena such as recruitment steps is an effective way to inhibit seizure generation in this model. The increased leukocyte adhesion dependent BBB permeability, and the seizure-dependent hyperexpression of adhesion molecules and vasodilatation suggest that seizure activity and leukocyte adhesion synergize in a selfamplifying cascade of events leading to chronic epilepsy. Inhibition of leukocytevascular interactions can have preventive as well as therapeutic effects in a mouse model of this debilitating disease.