Therapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis

Abstract

Abstract-Multiple Sclerosis (MS) is a demyelinating disease which causes inflammation, demyelination, and axonal injury. Currently, there is no cure for the disease. The endocannabinoid system has recently emerged as a promising therapeutic target for MS. The protective mechanisms of cannabinoids are thought to be mediated by the activation of the cannabinoid type 1 (CB1) and type 2 (CB2) receptors expressed primarily in neurons and immune cells, respectively. However, the molecular mechanisms and the contribution of each receptor in ameliorating disease progression are still debatable. Although CB1 and CB2 receptors are expressed in oligodendrocytes, the myelin producing cells in the central nervous system, the role of cannabinoids in oligodendrocyte survival has not been well investigated. Using primary cultures of mature oligodendrocytes, we tested the effect of a novel synthetic cannabinoid CB52 on oligodendrocyte toxicity induced by peroxynitrite, the primary toxic species released by microglia. Interestingly, we found that CB52 is more potent than a number of broad and selective CB1 and CB2 agonists in protecting oligodendrocytes against peroxynitrite-induced toxicity. The protection provided by CB52 is likely due to its reduction of ERK1/2 phosphorylation and reactive oxygen species (ROS) generation in these cells. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we found that CB52 reduces microglia activation, nitrotyrosine formation, T cell infiltration, oligodendrocyte toxicity, myelin loss and axonal damage in the mouse spinal cord white matter and alleviates the clinical scores when given either before or after disease onset. These effects are reversed by the CB1 receptor antagonist, but not by the CB2 receptor antagonist, suggesting that the activation of CB1 receptors contributes significantly to the anti-inflammatory and neuroprotective effects of cannabinoids on MS. Published by Elsevier Ltd. on behalf of IBRO.

Activation of CB2 receptor is required for the therapeutic effect of ABHD6 inhibition in experimental autoimmune encephalomyelitis

“…These results further validated our findings that the therapeutic effect of WWL70 is mediated by activation of CB2 receptors. However, the studies from our lab and others have also demonstrated that the anti-inflammatory and neuroprotective effects of several cannabinoid agonists in the EAE mouse model are mediated by CB1R, but not CB2R activation (de Lago et al, 2012;Pryce and Baker, 2007;Ribeiro et al, 2013). These results point to the complexity of various cannabinoid signaling pathways in the immune regulation under different conditions.…”

Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity

“…In the brain of lipopolysaccharide (LPS)-treated (Marchalant et al, 2007) or in the spinal cord of paclitaxel-treated rats (Burgos et al, 2012) the CB1/CB2 receptor agonist WIN-55212-2 reduced the pro-inflammatory activity of microglia cells. In the mouse model of experimental autoimmune encephalomyelitis the synthetic agonist CB52 slowed down Ribeiro et al (2013), while the cannabinoid receptor antagonist SR141716A accelerated the progression of neuroinflammatory changes (Lou et al, 2018), both in a CB1 receptor-dependent manner. In another study, delta-9-tetrahydrocannabinol (THC) prevented 3,4-Methylendioxy-N-methylamphetamin (MDMA) induced glial activation in wild-type (WT) control mice but not in mice with either genetic or pharmacologic blockade of CB1 receptors (Touriño et al, 2010), further supporting the importance of CB1 receptors in the anti-inflammatory effect of cannabinoid agonists.…”

Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis

“…This type of distribution supports the prospect that anti-inflammatory and immunosuppressive CB2R-selective drugs without psychoactivity can be developed for the management of chronic inflammatory diseases. Indeed, selective CB2R agonists display beneficial anti-inflammatory and positive effects on experimental autoimmune encephalomyelitis (Kong et al 2014;Ribeiro et al 2013), atherosclerosis (Chiurchiu et al 2014), endotoxininduced sepsis (Gui et al 2013), cystitis , liver disease (Guillot et al 2014), pancreatitis (Michler et al 2013), inflammatory bowel disease (Storr et al 2009), and uveitis (Toguri et al 2014).…”