Using immunocytochemistry and ELISA, we investigated the production of interleukin (IL)-1␤ in the rat hippocampus after focal application of kainic acid inducing electroencephalographic (EEG) seizures and CA3 neuronal cell loss. Next, we studied whether EEG seizures per se induced IL-1␤ and microglia changes in the hippocampus using bicuculline as a nonexcitotoxic convulsant agent. Finally, to address the functional role of this cytokine, we measured the effect of human recombinant (hr)IL-1␤ on seizure activity as one marker of the response to kainate.Three and 24 hr after unilateral intrahippocampal application of 0.19 nmol of kainate, IL-1␤ immunoreactivity was enhanced in glia in the injected and the contralateral hippocampi. At 24 hr, IL-1␤ concentration increased by 16-fold ( p Ͻ 0.01) in the injected hippocampus. Reactive microglia was enhanced with a pattern similar to IL-1␤ immunoreactivity. Intrahippocampal application of 0.77 nmol of bicuculline methiodide, which induces EEG seizures but not cell loss, enhanced IL-1␤ immunoreactivity and microglia, although to a less extent and for a shorter time compared with kainate. One nanogram of (hr)IL-1␤ intrahippocampally injected 10 min before kainate enhanced by 226% the time spent in seizures ( p Ͻ 0.01). This effect was blocked by coinjection of 1 g (hr)IL-1␤ receptor antagonist or 0.1 ng of 3-((ϩ)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate, selective antagonists of IL-1␤ and NMDA receptors, respectively.Thus, convulsant and/or excitotoxic stimuli increase the production of IL-1␤ in microglia-like cells in the hippocampus. In addition, exogenous application of IL-1␤ prolongs kainateinduced hippocampal EEG seizures by enhancing glutamatergic neurotransmission.

IL-1␤ and its endogenous receptor antagonist (IL-1RaIL-1␤ appears to be involved in neuronal network excitability because it affects the turnover and release of various neurotransmitters (1) and the expression of neuropeptides and neurotrophic factors (3-5) and alters synaptic transmission and ionic currents (6-9) in several rodent forebrain regions.Convulsant stimuli increase the production of IL-1␤, its naturally occurring receptor antagonist (IL-1Ra), and IL-1R type I and II predominantly in glia in rodent central nervous system within hours of seizure induction (10-15).We recently showed that IL-1␤ prolongs hippocampal electroencephalographic (EEG) seizures in a N-methyl-D-aspartate receptor-dependent manner, and this action was blocked by .In this study, we investigated whether IL-1Ra has anticonvulsant properties in rodents. We found that intracerebral application of recombinant IL-1Ra or its endogenous overexpression in astrocytes potently inhibited behavioral and EEG seizures induced by bicuculline methiodide in mice. This effect was mediated specifically by IL-1R type I, because IL-1Ra was ineffective in knockout mice deficient in these receptors.Thus, the functional interaction between brain-born IL-1␤ and IL-1Ra during seizures, (i) may play a critical role in the physiopathological functions of IL-1␤, and (ii) may significantly affect the maintenance and spread of seizures. Materials and MethodsAnimals. Procedures involving animals and their care were conducted in conformity with institutional guidelines in compliance with national and international laws and policies (4D. L. N. 116, Gazzetta Ufficiale, supplement 40, 18-2-1992 and European

Cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha can play pathogenetic or protective roles in stroke. They are increased in the brain after experimental ischemia and in the CSF of patients with stroke. However, their presence in the periphery is still controversial. To determine the source and time-course of cytokines in blood of stroke patients, IL-6 and TNF-alpha release from blood cells and serum levels were determined in 40 patients on days 1 through 2, 4, 10, 30, and 90 after stroke. Twenty healthy age-matched volunteers were used as controls. IL-6 and TNF-alpha release from stimulated blood cells was increased in stroke patients, compared to controls. A peak response (+224%) was observed at day 4 for IL-6, while TNF-alpha release was largely and significantly increased (about three-fold compared to controls) from day 1 to 2 until day 90 after stroke. The increase in IL-6 release was significantly higher in ischemic, compared to hemorrhagic strokes, at days 1 and 4. Circulating IL-6 was increased at each time point. The ischemic processes in the CNS induces a long-lasting activation of IL-6 and TNF-alpha production in peripheral blood cells, which are a major source of serum cytokines after stroke.