Cannabinoids and experimental models of multiple sclerosis

Kubajewska, Ilona; Constantinescu, Cris S.

doi:10.1016/j.imbio.2009.08.004

Cited by 34 publications

(25 citation statements)

References 232 publications

(214 reference statements)

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“…Several cannabinoid receptors have been described, that is, the classic cannabinoid receptor 1 (GPR) and GPR, the previously orphaned G-protein receptors GPR18 and GPR55, various ion channels, and intracellular peroxisome proliferator-activated receptor-␥ (reviewed in Pertwee et al 1 and Console-Bram 2 ). The 2 classic cannabinoid receptors, CB1R and CB2R, have different distribution and functions (reviewed in Kubajewska and Constantinescu 3 and Basu and Dittel 4 ). CB1R is abundantly expressed on CNS and peripheral neurons and involved in neural functions.…”

Section: Introductionmentioning

confidence: 99%

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Adhikary¹,

Kocieda

Yen

et al. 2012

Blood

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Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators. Previous studies reported that CB2R signaling also reduces leukocyte migration. Migration of dendritic cells (DCs) to various sites is required for their activation and for the initiation of adaptive immune responses. Here, we report for the first time that CB2R signaling affects DC migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase 9 (MMP-9) expression. Reduced MMP-9 production by DCs results in decreased migration to draining lymph nodes in vivo and in vitro in the matrigel migration assay. The effect on Mmp-9 expression is mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to Mmp-9 promoter activator protein 1 sites. We postulate that, by dampening production of MMP-9 and subsequent MMP-9-dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs. IntroductionThe cannabinoid system consists of cannabinoid receptors and their ligands, including endocannabinoids, synthetic cannabinoid receptor agonists and antagonists, and phytocannabinoids. Several cannabinoid receptors have been described, that is, the classic cannabinoid receptor 1 (GPR) and GPR, the previously orphaned G-protein receptors GPR18 and GPR55, various ion channels, and intracellular peroxisome proliferator-activated receptor-␥ (reviewed in Pertwee et al 1 and Console-Bram 2 ). The 2 classic cannabinoid receptors, CB1R and CB2R, have different distribution and functions (reviewed in Kubajewska and Constantinescu 3 and Basu and Dittel 4 ). CB1R is abundantly expressed on CNS and peripheral neurons and involved in neural functions. In contrast, CB2R is mostly expressed on immune cells and involved in immunoregulation. Administration of CB2R-selective agonists in models of inflammatory and autoimmune diseases such as systemic sclerosis, experimental autoimmune uveoretinitis, inflammatory bowel diseases, and experimental autoimmune encephalomyelitis (EAE) resulted in attenuation of clinical disease (reviewed in Basu and Dittel 4 ). CB2R agonists also have been reported to have a beneficial effect in models of CNS injury such as cerebral infarction and spinal cord injury. [5][6][7][8] In addition to effects on clinical outcome, CB2R agonists reduced the levels of inflammatory mediators in various experimental models. [8][9][10] A possible mechanism for the anti-inflammatory effect of CB2R signaling is the direct action of CB2R agonists on immune cells. In vitro studies indicated that CB2R signaling inhibited the production of proinflammatory cytokines such as TNF␣, IL-6, IL-2, and IFN-␥ by ac...

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Section: Introductionmentioning

confidence: 99%

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Adhikary¹,

Kocieda

Yen

et al. 2012

Blood

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“…Furthermore, various experimental models have shown that the activation of cannabinoid receptors in the inflammatory demyelinative process characterizing MS may cause a neuroprotective effect through a CB 1 receptor-mediated inhibition of excitotoxicity and through a CB 2 receptor-mediated inhibition of neuroinflammation [Sánchez and García-Merino, 2012;Kubajewska and Constantinescu, 2010;Gowran et al 2010]. In a study of patients with MS by Jean-Gilles and colleagues, increased endocannabinoid levels were found in the plasma of patients that was attributed to a neuroprotective regulatory mechanism of the endocannabinoid system [JeanGilles et al 2009].…”

Section: The Endocannabinoid Systemmentioning

confidence: 99%

Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity

Leussink

Husseini

Warnke

et al. 2012

Ther Adv Neurol Disord

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A large proportion of patients with multiple sclerosis (MS) have spasticity, which has a marked impact on their quality of life. Anecdotal evidence suggests a beneficial effect of cannabis on spasticity as well as pain. Recently, randomized, double-blind, placebocontrolled studies have confirmed the clinical efficacy of cannabinoids for the treatment of spasticity in patients with MS. Based on these data, nabiximols (Sativex), a 1:1 mix of ∆-9-tetrahydrocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, received approval for treating MS-related spasticity in various countries around the globe. In this article we review the current understanding of cannabinoid biology and the value of cannabinoids as a symptomatic treatment option addressing spasticity in patients with MS.

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“…Toxicity was then evaluated using Alamar Blue. CB52 was able to attenuate zinc toxicity in mature oligdendrocytes and this effect was partially blocked by the CB2 antagonist but not the CB1 antagonist (n = 5; presenting cells and release inflammatory mediators (Kubajewska and Constantinescu, 2010). At 30 days after EAE induction, the infiltration of CD4 + T cells was clearly observed in the spinal cord white matter, which was almost completely blocked by treatment with CB52 either before (Fig.…”

Section: Eae Is Primarily Mediated By the Infiltration Of Cd4mentioning

confidence: 85%

“…The first study using cannabinoids in this model system showed that D 9 -tetrahydrocannabinol (THC), the main active component of the cannabis plant, has immunomodulatory functions, as indicated by the reduced numbers of infiltrating cells in the spinal cord (Lyman et al, 1989). Following this study many groups have further demonstrated the beneficial effects of various cannabinoids in different animal models of MS (Kubajewska and Constantinescu, 2010). The beneficial effects of cannabinoids are attributable to their activation of cannabinoid type 1 (CB1) and CB2 receptors (Matsuda et al, 1990;Munro et al, 1993), although increasing evidence points to the contribution by novel receptors and receptor-independent mechanisms (Puffenbarger et al, 2000;Kaplan et al, 2003Kaplan et al, , 2008Walter et al, 2003;Kozela et al, 2010).…”

Section: Introductionmentioning

confidence: 95%

“…Although the results obtained by CB52 in vitro and in vivo seem to be paradoxical, several possibilities might be taken into consideration. First, the expression of CB1/CB2 receptors in virtually all the immune cells, neurons and glia cells makes it difficult to sort out the specific role of these receptors in each cell type and the overall contribution of these receptors in vivo; Second, although our results have demonstrated that the protective effect of CB52 on peroxynitriteinduced toxicity to oligodendrocytes is partially mediated by CB2 receptor, it is unclear whether activation of CB1 receptor can be involved in other toxic conditions, for instance, the toxicity triggered by cytokines, chemokines or glutamate; Third, the CB2 receptors expressed in T cells are highly regulated by endogenous cannabinoid ligands in the CNS during EAE, and activation of these receptors does not seem to require exogenous agonists for the suppressive effects (Maresz et al, 2007;Kubajewska and Constantinescu, 2010). This idea is supported by a recent finding that HU-308, a CB2 receptor selective agonist, did not exact any protective effect in EAE (de Lago et al, 2012).…”

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confidence: 99%

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

Ribeiro

Wen

et al. 2013

Neuroscience

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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.

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Cannabinoids and experimental models of multiple sclerosis

Cited by 34 publications

References 232 publications

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity

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

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