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Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia.
Molina-Holgado F, Pinteaux E, Moore J, Molina-Holgado E, Guaza C, Gibson R, Rothwell NJ
J Neurosci. 2003;23( 16):6470-4.
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Abstract
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.
Keyword(s)
Animals; Cells, Cultured; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Cannabinoid; Support, Non-U.S. Gov't; agonists: Receptors, Drug; antagonists & inhibitors: Lipopolysaccharides; cytology: Neuroglia; cytology: Neurons; deficiency: Sialoglycoproteins; metabolism: Nitric Oxide; pharmacology: Anti-Inflammatory Agents; pharmacology: Bornanes; pharmacology: Cannabinoids; pharmacology: Neuroprotective Agents; pharmacology: Neurotoxins; pharmacology: Piperidines; pharmacology: Pyrazoles