Powerful Anticonvulsant Action of IL-1 Receptor Antagonist on Intracerebral Injection and Astrocytic Overexpression in Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 97; no. 21; pp. 11534 - 11539
• Main Authors: Vezzani, A., Moneta, D., Conti, M., Richichi, C., Ravizza, T., De Luigi, A., De Simoni, M. G., Sperk, G., Andell-Jonsson, S., Lundkvist, J., Iverfeldt, K., Bartfai, T.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 10-10-2000; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Anticonvulsants; Anticonvulsants - administration & dosage; Anticonvulsants - pharmacology; Astrocytes - metabolism; Biological Sciences; Brain; Cytokines; Genes, fos; Hippocampus; Hippocampus - metabolism; Hippocampus - physiopathology; Immunohistochemistry; Interleukin 1 Receptor Antagonist Protein; Interleukin-1 - administration & dosage; Interleukin-1 - pharmacology; Male; Messenger RNA; Mice; Mice, Inbred CBA; Mice, Transgenic; Neurology; Neuroscience; Pharmacology; Receptors; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; RNA, Messenger - genetics; Rodents; Seizures; Seizures - prevention & control; Sialoglycoproteins - administration & dosage; Sialoglycoproteins - pharmacology; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.190206797

IL-1β and its endogenous receptor antagonist (IL-1Ra) are rapidly induced by seizures in the rodent hippocampus. Exogenously applied IL-1β prolongs seizures in an IL-1R type I-mediated manner. This effect depends on N-methyl-D-aspartate receptor activation. We report here that intrahippocampal application of recombinant IL-1Ra or its selective endogenous overexpression in astrocytes under the control of glial acidic fibrillary protein promoter potently inhibits motor and electroencephalographic seizures induced by bicuculline methiodide in mice. Accordingly, transgenic mice show a reduced seizure-related c-fos mRNA expression in various forebrain areas compared with their wild-type littermates. Recombinant IL-1Ra was ineffective in mice deficient in IL-1R type I, having per se a delayed onset to generalized convulsions. These results demonstrate that IL-1Ra mediates potent anticonvulsant effects acting on IL-1R type I and suggest that the balance between brain IL-1β and IL-1Ra represents a crucial mechanism to control seizure generalization.