Society for Neuroscience, Journal of Neuroscience, 16(23), p. 6470-6474, 2003
DOI: 10.1523/jneurosci.23-16-06470.2003
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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 CB1and CB2receptors modulate release of endogenous IL-1ra from primary cultured glial cells. Activation of CB1or CB2receptors increased lipopolysaccharide-induced IL-1ra release, and specific CB1or CB2antagonists 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 CB1and CB2receptor-dependent pathways.