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

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.

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

“…The CB 1 receptor regulates motor behavior in the basal ganglia via mediating both excitatory and inhibitory inputs to the SN reticulate and globus pallidus (53) as well as short-and long-term synaptic plasticity through suppressing the release of neurotransmitters, such as glutamate and GABA (54,55). Additionally, cannabinoids modulate inflammatory responses by regulating microglial function through both receptor-dependent and -independent mechanisms (39,(56)(57)(58).…”

Cannabinoids and Epilepsy

“…Δ9-THC has antioxidant effects in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-and N-methyl-D-aspartate-mediated cytotoxicity models via a CB 1 R-independent mechanism [87]. Cannabinoids reduce neuronal and glial release of the proinflammatory cytokines tumor necrosis factor-α, NO, interleukin (IL)-1 and IL-6 [88][89][90][91][92][93], and increase release of anti-inflammatory cytokines IL-4, IL-10, and IL-1 receptor antagonist (IL-1a) [94,95] via CB1R-and CB2R-dependent mechanisms in neurons and glia [94,95] (reviewed in [96]). Δ9-THC also transiently activates and desensitizes the transient receptor potential (TRP) channels TRPA1, TRPV1, and TRPV2 [97][98][99].…”

Astrocytes in endocannabinoid signalling

“…Earlier studies showed discrepancies in the expression of CB1Rs by astrocytes in culture (see [30]), which could arise from the well-known phenotypic changes in astrocytes in different culture conditions. Indeed, several studies indicated the presence of such changes in astrocytes in culture and in situ [30][31][32][33][34][35] This activation increased astrocyte Ca 2þ levels through the mobilization of Ca 2þ from internal stores [9]. The intracellular signalling pathway underlying this effect exhibited specific characteristics.…”