Interleukin-l beta immunoreactivity and microglia are enhanced in the rat hippocampus by focal kainate application: Functional evidence for enhancement of electrographic seizures

Using immunocytochemistry and ELISA, we investigated the production of inte rleukin (IL)-1 beta in the rat hippocampus after focal application of kaini c acid inducing electroencephalographic (EEG) seizures and CA3 neuronal cel l loss. Next, we studied whether EEG seizures per se induced IL-1 beta 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 beta on seizure activ ity as one marker of the response to kainate. Three and 24 hr after unilateral intrahippocampal application of 0.19 nmol of kainate, IL-1 beta immunoreactivity was enhanced in glia in the injected and the contralateral hippocampi. At 24 hr, IL-1 beta concentration increa sed by 16-fold (p < 0.01) in the injected hippocampus. Reactive microglia w as enhanced with a pattern similar to IL-1 beta immunoreactivity. Intrahipp ocampal application of 0.77 nmol of bicuculline methiodide, which induces E EG seizures but not cell loss, enhanced IL-1 beta immunoreactivity and micr oglia, although to a less extent and for a shorter time compared with kaina te. One nanogram of (hr)IL-1 beta intrahippocampally injected 10 min before kainate enhanced by 226% the time spent in seizures (p < 0.01). This effec t was blocked by coinjection of 1 mu g (hr)IL-1 beta receptor antagonist or 0.1 ng of 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate, selective antagonists of IL-1 beta and NMDA receptors, respectively. Thus, convulsant and/or excitotoxic stimuli increase the production of IL-1 beta in microglia-like cells in the hippocampus. In addition, exogenous ap plication of IL-1 beta prolongs kainate-induced hippocampal EEG seizures by enhancing glutamatergic neurotransmission.