Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

Arévalo-Martı́n, Ángel; Vela, José Miguel; Molina‐Holgado, Eduardo; Borrell, José; Guaza, Carmen

doi:10.1523/jneurosci.23-07-02511.2003

Cited by 290 publications

(209 citation statements)

References 37 publications

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“…The activation of CB1 receptors probably mediates the neuroprotective effects of Δ 9 -THC as this receptor fulfils an important role in the defence against excitotoxicity (Marsicano et al, 2003) and excitotoxic mechanisms are prominent in TMEV-IDD (Docagne et al, 2007). Nevertheless, the participation of CB2 receptors is not unexpected given their key involvement in the control of glial activation and given that inflammatory events are also important in TMEV-IDD mice (Arévalo-Martín et al, 2003;. Indeed, it was previously demonstrated that Δ 9 -THC suppressed CNS autoimmune inflammation with the participation of both CB1 and CB2 receptors in CREAE mice (Maresz et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Preclinical studies have demonstrated that cannabinoids can alleviate MS-associated symptoms, such as spasticity (Baker et al, 2000), and they exhibit anti-inflammatory (Arévalo-Martín et al, 2003;Croxford and Miller, 2003), antioxidant, anti-excitotoxic and neuroprotective properties (Pryce et al, 2003;Fernández-Ruiz et al, 2010;Loría et al, 2010). Cannabinoids are also protective to oligodendrocytes in vitro and in vivo (Molina-Holgado et al, 2002;Gómez et al, 2010;Mecha et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

Feliú

Moreno-Martet

Mecha

et al. 2015

British J Pharmacology

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BACKGROUND AND PURPOSE Sativex® is an oromucosal spray, containing equivalent amounts of Δ 9-tetrahydrocannabinol (Δ 9 -THC) and cannabidiol (CBD)-botanical drug substance (BDS), which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS). In this study, we investigated whether Sativex may also serve as a disease-modifying agent in the Theiler's murine encephalomyelitis virus-induced demyelinating disease model of MS. EXPERIMENTAL APPROACHA Sativex-like combination of phytocannabinoids and each phytocannabinoid alone were administered to mice once they had established MS-like symptoms. Motor activity and the putative targets of these cannabinoids were assessed to evaluate therapeutic efficacy. The accumulation of chondroitin sulfate proteoglycans (CSPGs) and astrogliosis were assessed in the spinal cord and the effect of Sativex on CSPGs production was evaluated in astrocyte cultures. KEY RESULTSSativex improved motor activity -reduced CNS infiltrates, microglial activity, axonal damage -and restored myelin morphology. Similarly, we found weaker vascular cell adhesion molecule-1 staining and IL-1β gene expression but an up-regulation of arginase-1. The astrogliosis and accumulation of CSPGs in the spinal cord in vehicle-infected animals were decreased by Sativex, as was the synthesis and release of CSPGs by astrocytes in culture. We found that CBD-BDS alone alleviated motor deterioration to a similar extent as Sativex, acting through PPARγ receptors whereas Δ 9 -THC-BDS produced weaker effects, acting through CB2 and primarily CB1 receptors. CONCLUSIONS AND IMPLICATIONSThe data support the therapeutic potential of Sativex to slow MS progression and its relevance in CNS repair. -tetrahydrocannabinol-botanical drug substance; Arg-1, arginase-1; CBD-BDS, cannabidiol-botanical drug substance; CSPGs, chondroitin sulfate proteoglycans; ECM, extracellular matrix; GAG chains, glycosaminoglycan chains; OPCs, oligodendrocyte precursor cells; TMEV-IDD, Theiler's murine encephalomyelitis virus-induced demyelinating disease; VCAM-1, vascular cell adhesion molecule-1; Sativex, Sativex-like combination of phytocannabinoids; XT-I, xylosyltransferase-I Abbreviations

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

Feliú

Moreno-Martet

Mecha

et al. 2015

British J Pharmacology

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“…It is interesting to note that JWH-015 was recently found to improve the neurologic defect induced by Theiler's virus infection in which decreased numbers of CD4 + infiltrating T cells were noted in the spinal cord [37]. Although the precise mechanism of action of JWH-015 was unknown, the authors suggested that JWH-015 and other cannabinoids may decrease the number of CD4 + T cells thereby enhancing the myelin repair.…”

Section: Discussionmentioning

confidence: 99%

CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: Potential role for CB2-selective ligands as immunosuppressive agents

Lombard

Nagarkatti

2007

Clinical Immunology

105

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Cannabinoids are known to interact with CB1 and CB2 receptors expressed in the nervous and immune system, respectively and mediate a wide range of effects, including anti-inflammatory properties. However, cannabinoids that bind CB1 are also psychoactive thereby limiting their clinical use. In this study, we investigated the immunosuppressive properties of JWH-015, a synthetic CB2-selective agonist. We found that JWH-015 triggered apoptosis in thymocytes in vitro and inhibited the proliferative response of T and B cells to mitogens through induction of apoptosis. JWH-015 induced cross-talk between extrinsic and intrinsic pathways of apoptosis involving caspase-8, caspase-9, and caspase-3 as well as loss of mitochondrial membrane potential. Finally, administration of JWH-015 in vivo caused thymic atrophy, apoptosis, and decreased peripheral T cell response to mitogens. Together, this study suggests that CB2 selective agonists, devoid of psychotropic effect, may serve as novel anti-inflammatory/immunosuppressive agents.

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“…In addition, administration of synthetic cannabinoids ameliorated the tremor and spasticity in mice with chronic relapsing EAE, through a CB 1 -mediated mechanism (Baker et al, 2000). Cannabinoid receptor agonists also improved neurological deficits in the Theiler's murine encephalitis virus model as a result of both a reduction in CNS inflammation and extensive remyelination (Arevalo-Martin et al, 2003).…”

Section: Introductionmentioning

confidence: 97%

Cannabinoid CB₁and CB₂Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

Benito¹,

Romero²,

Tolón³

et al. 2007

J. Neurosci.

241

175

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Increasing evidence supports the idea of a beneficial effect of cannabinoid compounds for the treatment of multiple sclerosis (MS).However, most experimental data come from animal models of MS. We investigated the status of cannabinoid CB 1 and CB 2 receptors and fatty acid amide hydrolase (FAAH) enzyme in brain tissue samples obtained from MS patients. Areas of demyelination were identified and classified as active, chronic, and inactive plaques. CB 1 and CB 2 receptors and FAAH densities and cellular sites of expression were examined using immunohistochemistry and immunofluorescence. In MS samples, cannabinoid CB 1 receptors were expressed by cortical neurons, oligodendrocytes, and also oligodendrocyte precursor cells, demonstrated using double immunofluorescence with antibodies against the CB 1 receptor with antibodies against type 2 microtubule-associated protein, myelin basic protein, and the platelet-derived growth factor receptor-␣, respectively. CB 1 receptors were also present in macrophages and infiltrated T-lymphocytes. Conversely, CB 2 receptors were present in T-lymphocytes, astrocytes, and perivascular and reactive microglia (major histocompatibility complex class-II positive) in MS plaques. Specifically, CB 2 -positive microglial cells were evenly distributed within active plaques but were located in the periphery of chronic active plaques. FAAH expression was restricted to neurons and hypertrophic astrocytes. As seen for other neuroinflammatory conditions, selective glial expression of cannabinoid CB 1 and CB 2 receptors and FAAH enzyme is induced in MS, thus supporting a role for the endocannabinoid system in the pathogenesis and/or evolution of this disease.

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Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

Cited by 290 publications

References 37 publications

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: Potential role for CB2-selective ligands as immunosuppressive agents

Cannabinoid CB₁and CB₂Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

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Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

Cited by 290 publications

References 37 publications

A Sativex®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

A Sativex®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: Potential role for CB2-selective ligands as immunosuppressive agents

Cannabinoid CB1and CB2Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis

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A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

A Sativex^®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

Cannabinoid CB₁and CB₂Receptors and Fatty Acid Amide Hydrolase Are Specific Markers of Plaque Cell Subtypes in Human Multiple Sclerosis