Interleukin-1beta 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 interleukin (IL)-1beta 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-1beta 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-1beta 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-1beta immunoreactivity was enhanced in glia in the injected and the contralateral hippocampi. At 24 hr, IL-1beta concentration increased by 16-fold (p < 0.01) in the injected hippocampus. Reactive microglia was enhanced with a pattern similar to IL-1beta immunoreactivity. Intrahippocampal application of 0.77 nmol of bicuculline methiodide, which induces EEG seizures but not cell loss, enhanced IL-1beta immunoreactivity and microglia, although to a less extent and for a shorter time compared with kainate. One nanogram of (hr)IL-1beta intrahippocampally injected 10 min before kainate enhanced by 226% the time spent in seizures (p < 0.01). This effect was blocked by coinjection of 1 microgram (hr)IL-1beta receptor antagonist or 0.1 ng of 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate, selective antagonists of IL-1beta and NMDA receptors, respectively. Thus, convulsant and/or excitotoxic stimuli increase the production of IL-1beta in microglia-like cells in the hippocampus. In addition, exogenous application of IL-1beta prolongs kainate-induced hippocampal EEG seizures by enhancing glutamatergic neurotransmission.
Vezzani
A
A
Laboratory of Experimental Neurology, Department of Neuroscience, Istituto di Ricerche Farmacologiche "Mario Negri," 20157 Milan, Italy.
Conti
M
M
De Luigi
A
A
Ravizza
T
T
Moneta
D
D
Marchesi
F
F
De Simoni
M G
MG
D000818:Animals; D000906:Antibodies; D000927:Anticonvulsants / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D002452:Cell Count; D004569:Electroencephalography; D004797:Enzyme-Linked Immunosorbent Assay; D004827:Epilepsy / Q000139:chemically induced / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry* / Q000166:cytology* / Q000187:drug effects; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000032:analysis* / Q000276:immunology / Q000494:pharmacology; D007608:Kainic Acid; D008297:Male; D017628:Microglia / Q000166:cytology* / Q000187:drug effects; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000494:pharmacology
D000906:Antibodies; D000927:Anticonvulsants; D018501:Antirheumatic Agents; D018690:Excitatory Amino Acid Agonists; D018756:GABA Antagonists; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D010879:Piperazines; D012795:Sialoglycoproteins; D018698:Glutamic Acid; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D007608:Kainic Acid; D001640:Bicuculline