Abstracts

RATIONALE: Severe, long lasting seizures induce neuronal loss, gliosis and plastic changes, supposed to generate a chronic epileptic focus. However, signals that activate glia during or after seizures are still unknown. Here we studied the expression or activation of molecules involved in immune or inflammatory processes, at various time-points after limbic status epilepticus (SE) in rats, and in human hippocampi, surgically removed from patients with temporal lobe epilepsy. METHODS: 1- SE was induced in rats by intra-cerebral injection of kainate (sham-injected rats received saline). Sacrifice occurred between 1 and 15 days after SE. Cytokines were measured by bio-assay. The expression of the nuclear transcription factor NFkappaB and of the major histocompatibility complex (MHC) antigens was studied in lesioned hippocampi by immunocytochemistry. The nuclear activation of NFkappaB was evaluated by electrophoretic mobility shift assay. 2- Human hippocampi removed after surgery were fixed, frozen and cut. A double immuno-labeling was performed to localize inflammation or immune-related molecules in neurons, astrocytes or microglia. RESULTS: 1- In rat hippocampi, we observed : i) 1-2 days after SE, an important TNFa release, an over-expression of NFkappaB in some neurons and an increase of its nuclear translocation and activation ; ii) 4-8 days after SE, a strong activation of microglia expressing MHC class I and II, an intense NFkappaB staining in reactive astrocytes located in lesioned areas, while TNFa release and NFkappaB activity were still elevated ; iii) 2 weeks after SE, a persistent staining of NFkappaB and MHC in reactive astrocytes and microglia, respectively. 2- In human hippocampi, NFkappaB expression was intense in astrocytes, and more or less important in pyramidal neurons of lesioned areas. In some patients, microglial cells exhibited characteristic patterns of inflammatory state. CONCLUSIONS: These long-lasting inflammatory responses, via redundant interactions between neurons, astrocytes and microglia, induce the release of both toxic or protective molecules. Further studies might produce new strategies in the treatment of chronic epilepsy.