Abstracts

RATIONALE: In neurodegenerative diseases, activated glia is known to contribute to neurotoxicity by generating cytokines, reactive oxygen intermediates, nitric oxide (NO) and glutamate receptor agonists. Similar mechanisms have been suggested for epilepsies associated with neuronal loss.
Furthermore, according to the epileptogenic glial scar hypothesis, reactive astrocytes in injured areas are supposed to participate in secondary epileptogenesis, through the release of growth factors that support neural reorganization.
Here we studied the role of glial cells in both inflammatory reactions and morphological changes after seizures, in rodent experimental models and in the hippocampus of patients with mesial temporal lobe epilepsy (MTLE).
METHODS: Two animal models of epilepsy were used : mice organotypic hippocampal cultures treated with kainic acid (KA) and KA-induced status epilepticus in rats. Human hippocampi were obtained in patients with MTLE, having benefited from hippocampectomy.
Using immunocytochemistry, we looked for the expression of inflammatory and immune relative molecules (transcription factor NFkappaB, Tumor Necrosis Factor alpha, inducible Nitric Oxide Synthase, macrophage antigens) and of vimentin, a protein of intermediate filaments, usually expressed in radial, immature astroglia, but also expressed in the pathologic adult brain.
RESULTS: Models of KA-induced epilepsy showed that rapidly after seizures, pyramidal neurons overexpressed NFkappaB, then transiently expressed TNFalpha. Microglia, reactive after a few hours, expressed various surface antigens and iNOS. Later, astrocytes in lesioned areas were densely positive for NFkappaB, iNOS and vimentin. In vivo, the glial expression of immune and inflammatory related molecules was obvious at least 2 weeks after status epilepticus.
In human chronic epileptic focus, similar expressions were observed. Interestingly, in patients with MTLE associated with hippocampal sclerosis and dentate granule cell dispersion, vimentin was strongly expressed in astrocytes that showed a radial organization in the granular layer.
CONCLUSIONS: These results show that glial activation lasts a long time after a severe epileptic event. It is likely that firing neurons initiate the glial reaction by various signals and that, in the chronic focus, repeated seizures maintain gliosis. Therefore, the glial release of proinflammatory cytokines and toxic molecules could worsen neurodegeneration and nurture the glial scar. Moreover, the reexpression of vimentin by radial astroglia could participate in the migration and dispersion of newborn granule cells.