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The Journal of Neuroscience, July 23, 2003, 23(16):6470-6474

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BRIEF COMMUNICATION
Endogenous Interleukin-1 Receptor Antagonist Mediates Anti-Inflammatory and Neuroprotective Actions of Cannabinoids in Neurons and Glia

Francisco Molina-Holgado,1 Emmanuel Pinteaux,1 Jonathan D. Moore,1 Eduardo Molina-Holgado,2 Carmen Guaza,2 Rosemary M. Gibson,1 and Nancy J. Rothwell1

1School of Biological Sciences, University of Manchester, Manchester M13 9PT, United Kingdom, and 2Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002 Madrid, Spain

Interleukin-1 receptor antagonist (IL-1ra) is an important anti-inflammatory cytokine that blocks all known actions of IL-1 and markedly protects against experimentally induced ischemic, excitotoxic, and traumatic brain insults. Cannabinoids (CBs) also exert potent anti-inflammatory and neuroprotective effects, but the mechanisms of their actions are unknown. Here we tested the hypothesis that the actions of CBs are mediated by endogenous IL-1ra. We report for the first time that both CB1 and CB2 receptors modulate release of endogenous IL-1ra from primary cultured glial cells. Activation of CB1 or CB2 receptors increased lipopolysaccharide-induced IL-1ra release, and specific CB1 or CB2 antagonists blocked lipopolysaccharide-induced production of IL-1ra from glial cells. Comparison of neuronal cultures from wild-type mice and mice lacking IL-1ra (knock-out) indicates that endogenous IL-1ra is essential for the neuro-protective effects of CBs against excessive activation of glutamate receptors (excitotoxicity) in response to S-AMPA or NMDA. Similarly, analysis of mixed glial cultures from IL-1ra knock-out mice indicates that endogenous IL-1ra is required for the CB-induced inhibition of nitric oxide production in response to bacterial lipopolysaccharide. These data suggest a novel neuroprotective mechanism of action for CBs in response to inflammatory or excitotoxic insults that is mediated by both CB1 and CB2 receptor-dependent pathways.

Key words: cytokine; cannabinoid; neuroprotection; IL-1ra; excitotoxicity; nitric oxide


Received Mar. 25, 2003; revised May. 13, 2003; accepted Jun. 2, 2003.






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