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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

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

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