Abstracts

Lithium-pilocarpine (li-pilo) status epilepticus (SE) leads to extended brain lesions, mainly in hippocampus, parahippocampal cortices, amygdala and thalamus. Neuronal damage underlies the genesis of a hyperexcitable circuit leading to spontaneous recurrent seizures (SRS). To better understand the role of the inflammatory response in the genesis of lesions, we characterized Interleukin1-[beta] (IL1-[beta]), Nuclear Factor-[kappa]B (NF-kB) and Cyclooxygenase-2 (COX-2) expression together with neurodegeneration in the li-pilo model in the adult rat. SE was induced by the injection of LiCl (3 meq/kg) followed 18h later by 25 mg/kg pilocarpine. Rats (4 per group) were sacrificed at 4, 12 and 24 h after SE onset (acute phase) and at 3 and 6 days after SE (latent phase). Brains were perfused and 40-[micro]m coronal sections were cut. The immunoreactivity for the inflammation factors IL1-[beta], NF-kB, COX-2 and for the astrocytic marker GFAP was studied and correlated with neuronal degeneration assessed with Fluoro-Jade B staining. Double immunostaining with markers for astrocytes (GFAP and GLUT1), neurons (MAP2), and activated microglia (B4-isolectin) was performed at all times. The immunohistochemical expression of IL1-[beta], NF-kB and COX-2 started by 12 h after SE, persisted for 24 h and returned to basal levels by 3 and 6 days. The expression of IL1-[beta], NF-kB and COX-2 occurred mainly in structures prone to develop neuronal damage, such as piriform and entorhinal cortex, amygdala, hippocampus, thalamus and septum, but also in hypothalamus. IL1-[beta] expression was detected in glial cells, COX-2 in neurons and NF-kB in both cell types. The distribution of Fluoro-Jade B-positive neurons was associated with IL1-[beta], NF-kB and COX-2 proteins expression during SE but not during the latent period while neurons were still degenerating. By 12 h, Fluoro-Jade B staining was strong in cerebral cortex, moderate in amygdala and dentate gyrus, weak in caudate-putamen, thalamus and hypothalamus and lacking in CA1-CA3 pyramidal cell layers. Between 12 and 24 h after SE, Fluoro-Jade B staining intensified in amygdala, and thalamus and appeared in CA1-CA3 areas. These data indicate that during the acute phase of li-pilo SE, glial cells and neurons participate in the selective vulnerability of some brain regions by inducing an inflammatory reaction mediated by molecules such as IL1-[beta], NF-kB and COX-2. The timing of expression of these factors and temporal sequence of neuronal damage are in good accordance with our previous reports showing the primary involvement of cerebral cortex, thalamus, amygdala and hilus, and delayed response in hippocampal pyramidal cell layers. Thus, inflammation factors appear to contribute to the pathophysiology of epilepsy by inducing neuronal death and astrocytic activation. (Supported by INSERM U 405 and Fondation de l[apos]Avenir)