Abstracts

Rationale: TBI is one of the major causes of acquired epileptogenesis, in which the appearance of spontaneous seizures can occur months or years after the primary injury. Studies in models of status epilepticus (SE)-induced epileptogenesis showed prominent and chronic production of the proinflammatory cytokine, interleukin(IL)-1β in glia in the areas of SE onset and seizures generalization. IL-1β promotes epileptic activity, contributes to neurodegeneration, and increases blood-brain-barrier (BBB) permeability suggesting that it plays a role in the mechanisms of epileptogenesis and ictogenesis. This study aimed to investigate the activation of IL-1β system and markers of innate and adaptive immunity in a rat model of PTE and compare it to SE. Methods: TBI was induced by lateral fluid-percussion. Controls underwent sham-operation (n=5 each group). The frontoparietal cortex, hippocampus and thalamus were analyzed at 6-24 h, 10 d, and 11 months (about 50 % of TBI rats have spontaneous seizures) post-TBI. The following markers were assessed from immunohistochemically stained sections: IL-1β, IL-1 receptor type 1 (R1), the pattern of microglia (CD-11b) and astrocyte (GFAP) activation, T-(CD3) and B-lymphocytes (CD45RA), monocytes/macrophages (ED-1), NK cells (NKR-P1A) and granulocytes (HIS48). Neuronal damage was assessed using Nissl and Fluoro Jade staining. BBB permeability was assessed by measuring parenchymal IgG. Results: In all areas analyzed, microglia and astrocytes showed morphological features of activated cells 6 h to 10 d after TBI, returning to their resting state at 11 months. IL-1β was expressed by activated microglia and astrocytes at 6 h after TBI. Only astrocytes expressed IL-1β at 24 h and 10 d post-TBI. IL-1R1 immunostaining was increased in activated astrocytes and in various neurons at 6 h to 10 d post-TBI. The induction of IL-1β/IL-1R1 was invariably found in areas of neurodegeneration and BBB leakage. No detectable IL-1β/IL-1R1 immunostaining was observed at 11 months post-TBI in rats with or without spontaneous seizures. Granulocytes were found at 6-24 h after TBI while abundant parenchymal macrophages were observed 24 h to 10 d after TBI. Scarse B and T-lymphocytes and NK cells were found only intravascularly. Conclusions: Similar to rats with SE, IL-1β was expressed in astrocytes in areas of neuropathology and BBB leakage during the first 10 d while the induction of IL-1β in microglia was more transient. Both astrocytes and neurons expressed IL-1R1 suggesting that they were the targets of IL-1β. Granulocytes and macrophages were the perypheral immune cells present in TBI brain. Even though our data show a remarkable inflammatory reaction at early post-TBI phase similar to that seen after SE, a notable difference as compared to SE rats is the lack of IL-1β/IL-1R1 expression in TBI rats with spontaneous seizures. This difference may be due to the low frequency of spontaneous seizures in PTE model as compared to SE model and to the prolonged time elapsed between the last spontaneous seizure in TBI rats and their sacrifice (20-52 days).