Powerful Anticonvulsant Action of Interleukin (IL)-1 Receptor Antagonist upon Intracerebral Injection and Astrocytic Overexpression in Mice
Abstract number :
1.075
Submission category :
Year :
2000
Submission ID :
635
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Annamaria Vezzani, Daniela Moneta, Mirko Conti, Cristina Richichi, Teresa Ravizza, Ada De Luigi, Maria Grazia De Simoni, Gunther Sperk, Seeve Andell-Jonsson, Johan Lundkvist, Kerstin Iverfeldt, Tamas Bartfai, Mario Negri Inst for Pharmacol Research, Milan
Rationale Proinflammatory cytokines are important soluble mediators of cellular communication in both physiologic and pathophysiologic states. IL-1 appears to play a significant role in neuronal network excitability. Interleukin(IL)-1 and its endogenous receptor antagonist (IL-1Ra) are rapidly induced by seizures in the rodent hippocampus predominantly in glia. We recently showed that IL-1 prolongs hippocampal EEG seizures by enhancing glutamatergic neurotrasmission and this action was blocked by IL-1Ra. In this study, we investigated whether IL-1Ra has anticonvulsant properties in rodents. Methods Seizures were induced by unilateral intrahippocampal injection of bicuculline methiodide in freely-moving mice. They were monitored by behavioral observation of tonic-clonic components and EEG analysis using chronically implanted depth electrodes. In situ hybridization of c-fos mRNA was done to identify the brain regions affected by seizures. Results We here report that intrahippocampal application of recombinant IL-1 prolongs bicuculline methiodide induced-seizures in mice in a IL-1 receptor (R)-type I-mediated manner. On the other hand, intrahippocampal injection of recombinant IL-1Ra or its endogenous over-expression in astrocytes under the control of glial acidic fibrillary protein promoter, potently inhibits motor and EEG seizures induced by bicuculline. Accordingly, transgenic mice show a reduced expression of c-fos mRNA after seizures in various forebrain areas compared to 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. Discussion These results demonstrate that IL-1Ra mediates potent anticonvulsant effects acting on IL-1R-type I and suggest that the balance between brain IL-1 and IL-1Ra represents a crucial mechanism to control seizure generalization. We suggest that pharmacological means that increase the IL-1Ra/IL-1 ratio may be useful in inhibiting seizures. This work was supported by Telethon Onlus Foundation (E. 1094)