Presentations

Abstract

Introduction:

Neuroinflammation is a pivotal factor in the pathogenesis of seizures and epileptogenesis. CD40L and its receptor CD40 are members of the TNF family and are elevated in chronic epilepsy, both after seizures and during post-status epilepticus. The primary objective of this research was to determine whether the negative modulation of CD40 limits neuroinflammation in a model of epilepsy.

Methods:

The pentylenetetrazole (PTZ) model of seizure or the pilocarpine model of status epilepticus (SE) were induced in adult male mice deficient of CD40 (CD40KO) and their respective age-gender controls. Seizures were analyzed clinically using Racine's score and electrophysiologically from local field potential recordings utilizing a silicone probe in the brain. In a group of mice, siRNACD40 or shRNA were injected into the brain before PTZ treatment. Following euthanization, brain specimens underwent histological and biochemical analysis. Secretory sCD40L and a group of cytokines and chemokines were analyzed using ELISA or the Meso-Scale Discovery platform. ANOVA, Student's t test and Z- scores were used for statistical analysis.

Results:

Our preliminary data indicates that CD40 and sCD40L increased after seizures and that intracerebral siRNACD40 limits both seizure susceptibility and sCD40L concentration in the hippocampus. In addition, CD40KO showed: a) a decreased concentration of pro-inflammatory KC/GRO, IL6 and TNF alpha and increased IL-10 after SE; b) reduction of seizure-induced gamma oscillations in hippocampus and recurrent seizures; and c) reduced chronic brain damage.

Conclusion:

These data suggest that CD40L-CD40 constitutes a key component in the initiation of the inflammatory cascade during the development of epilepsy.