Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation

Docagne, Fabián; Muñetón, Vilma; Clemente, Diego; Ali, Carine; Loría, Frida; Correa, Fernando; Hernangómez, Miriam; Mestre, Leyre; Vivien, Denis; Guaza, Carmen

doi:10.1016/j.mcn.2006.12.005

Cited by 99 publications

(70 citation statements)

References 38 publications

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“…disease in TMEV-IDD mice, with a major participation of CB1 receptors, even though blocking CB2 receptors partly prevented the benefits elicited by this phytocannabinoid. 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;.…”

Section: Discussionmentioning

confidence: 99%

“…once daily from days 70 to 80 post-infection when the signs of disease were evident. The duration of the treatment was based on previous studies using the TMEV-IDD model (Docagne et al, 2007) In all experiments and after 10 days of treatment, the motor activity was evaluated and the animals were killed with an overdose of anaesthetic for tissue collection.…”

Section: Pharmacological Treatmentsmentioning

confidence: 99%

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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: Pharmacological Treatmentsmentioning

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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“…Thus far, HU210 has been used in animal models to investigate neurogenesis (30) and multiple sclerosis (31) and was recently shown to prevent formation of preneoplastic lesions in mouse colon (32). However, HU210 treatment of xenograft-bearing mice has not been reported thus far.…”

Section: Discussionmentioning

confidence: 99%

Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma

Oesch

Walter

Wachtel

et al. 2009

Molecular Cancer Therapeutics

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Gene expression profiling has revealed that the gene coding for cannabinoid receptor 1 (CB1) is highly up-regulated in rhabdomyosarcoma biopsies bearing the typical chromosomal translocations PAX3/FKHR or PAX7/FKHR. Because cannabinoid receptor agonists are capable of reducing proliferation and inducing apoptosis in diverse cancer cells such as glioma, breast cancer, and melanoma, we evaluated whether CB1 is a potential drug target in rhabdomyosarcoma. Our study shows that treatment with the cannabinoid receptor agonists HU210 and Δ 9 -tetrahydrocannabinol lowers the viability of translocationpositive rhabdomyosarcoma cells through the induction of apoptosis. This effect relies on inhibition of AKT signaling and induction of the stress-associated transcription factor p8 because small interfering RNA-mediated down-regulation of p8 rescued cell viability upon cannabinoid treatment. Finally, treatment of xenografts with HU210 led to a significant suppression of tumor growth in vivo. These results support the notion that cannabinoid receptor agonists could represent a novel targeted approach for treatment of translocation-positive rhabdomyosarcoma.

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“…Arvanil, a synthetic AEA analog, acts against ouabain-induced excitotoxicity via CB 1 receptor activation and prevents neuronal cell death in vivo (29). HU210 displays neuroprotective activity against excitotoxicity in a multiple sclerosis model (30). WIN55,212-2 protects against ventral tegmental area DA neuronal death under ischemic conditions in vivo and in vitro (31).…”

Section: P Arkinson's Disease (Pd) Is a Common Neurodegenerativementioning

confidence: 99%

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

Chung

Bok

Huh

et al. 2011

The Journal of Immunology

108

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This study examined whether the cannabinoid receptor type 1 (CB1) receptor contributes to the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. MPTP induced significant loss of nigrostriatal DA neurons and microglial activation in the substantia nigra (SN), visualized with tyrosine hydroxylase or macrophage Ag complex-1 immunohistochemistry. Real-time PCR, ELISA, Western blotting, and immunohistochemistry disclosed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase, and subsequent reactive oxygen species production and oxidative damage of DNA and proteins in MPTP-treated SN, resulting in degeneration of DA neurons. Conversely, treatment with nonselective cannabinoid receptor agonists (WIN55,212-2 and HU210) led to increased survival of DA neurons in the SN, their fibers and dopamine levels in the striatum, and improved motor function. This neuroprotection by cannabinoids was accompanied by suppression of NADPH oxidase reactive oxygen species production and reduced expression of proinflammatory cytokines from activated microglia. Interestingly, cannabinoids protected DA neurons against 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia, but not in neuron-enriched mesencephalic cultures devoid of microglia. The observed neuroprotection and inhibition of microglial activation were reversed upon treatment with CB1 receptor selective antagonists AM251 and/or SR14,716A, confirming the involvement of the CB1 receptor. The present in vivo and in vitro findings clearly indicate that the CB1 receptor possesses anti-inflammatory properties and inhibits microglia-mediated oxidative stress. Our results collectively suggest that the cannabinoid system is beneficial for the treatment of Parkinson’s disease and other disorders associated with neuroinflammation and microglia-derived oxidative damage.

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Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation

Cited by 99 publications

References 38 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

Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma

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

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Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation

Cited by 99 publications

References 38 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

Cannabinoid receptor 1 is a potential drug target for treatment of translocation-positive rhabdomyosarcoma

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

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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