Viral models of multiple sclerosis: Neurodegeneration and demyelination in mice infected with Theiler's virus

Mecha, Míriam; Carrillo‐Salinas, Francisco; Mestre, Leyre; Feliú, Ana; Guaza, Carmen

doi:10.1016/j.pneurobio.2012.11.003

Cited by 84 publications

(96 citation statements)

References 236 publications

(242 reference statements)

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“…The approval of Sativex for treatment of spasticity and neuropathic pain in MS opens the door to study the therapeutic potential of Sativex as a disease-modifying agent. Accordingly, we have assessed the efficacy of Sativex in controlling disease progression in a model of primary progressive MS, the TMEV-IDD model (Mecha et al, 2013a).…”

Section: Discussionmentioning

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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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%

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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“…However, this notion has now been challenged by a wide number of studies that indicate that, under many circumstances, the brain and the immune system may communicate in a bidirectional manner. For example, in some autoimmune diseases, such as multiple sclerosis, the immune system is exposed to myelin antigens (Dittel et al, 1999;de Vos et al, 2002;Mecha et al, 2013). These antigens are presented by dendritic cells (DCs) to antigen-specific T cells, resulting in adaptive immune responses and consequent demyelination of the CNS (Dittel et al, 1999).…”

Section: How Does the Injured Brain Activate The Immune System?mentioning

confidence: 99%

Molecular dialogs between the ischemic brain and the peripheral immune system: Dualistic roles in injury and repair

Chen

Shi

et al. 2014

Progress in Neurobiology

172

144

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Immune and inflammatory responses actively modulate the pathophysiological processes of acute brain injuries such as stroke. Soon after the onset of stroke, signals such as brain-derived antigens, danger-associated molecular patterns (DAMPs), cytokines, and chemokines are released from the injured brain into the systemic circulation. The injured brain also communicates with peripheral organs through the parasympathetic and sympathetic branches of the autonomic nervous system. Many of these diverse signals not only activate resident immune cells in the brain, but also trigger robust immune responses in the periphery. Peripheral immune cells then migrate toward the site of injury and release additional cytokines, chemokines, and other molecules, causing further disruptive or protective effects in the ischemic brain. Bidirectional communication between the injured brain and the peripheral immune system is now known to regulate the progression of stroke pathology as well as tissue repair. In the end, this exquisitely coordinated crosstalk helps determine the fate of animals after stroke. This article reviews the literature on ischemic brain-derived signals through which peripheral immune responses are triggered, and the potential impact of these peripheral responses on brain injury and repair. Pharmacological strategies and cell-based therapies that target the dialogue between the brain and peripheral immune system show promise as potential novel treatments for stroke.

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“…Currently, these include: (1) demyelination models, such as cuprizone, ethidium bromide, or lysolecithin administration; (Fernandes et al, 1997; Woodruff and Franklin, 1999) (2) viral models, such as infection with Theiler murine encephalomyelitis virus or murine hepatitis viru ((Rodriguez, 1988; Sorensen et al, 1980); and (3) transgenic models, which can be used to knock-out or overexpress chemokines or and cytokines in a specific cell types (e.g. overexpression of IFNγ in astrocytes as well as conditional and targeted ablation of oligodendrocytes (OLs) (Kipp et al, 2012; Mecha et al, 2012). However, the oldest and most studied animal model of MS, experimental autoimmune encephalomyelitis (EAE), has been shown to most closely recapitulate MS pathogenesis (Baxter, 2007; Mangiardi et al, 2011; Sternberger et al, 1984; Wekerle et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair

Hasselmann

Karim

Khalaj

et al. 2017

Journal of Neuroscience Methods

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Background While many groups use experimental autoimmune encephalomyelitis (EAE) as a model to uncover therapeutic targets and understand the pathology underlying multiple sclerosis (MS), EAE protocol variability introduces discrepancies in central nervous system (CNS) pathogenesis and clinical disease, limiting the comparability between studies and slowing much-needed translational research. Optimized method Here we describe a detailed, reliable protocol for chronic EAE induction in C57BL/6 mice utilizing two injections of myelin oligodendrocyte glycoprotein (35–55) peptide mixed with Complete Freund’s Adjuvant and paired with pertussis toxin. Results The active MOG35–55 EAE protocol presented here induces ascending paralysis in 80–100% of induced mice. We observe: (1) consistent T cell immune activation, (2) robust CNS infiltration by peripheral immune cells, and (3) perivascular demyelinating lesions concurrent with axon damage in the spinal cord and various brain regions, including the optic nerve, cortex, hippocampus, internal capsules, and the cerebellum. Comparison with existing method(s) Lack of detailed protocols, combined with variability between laboratories, make EAE results difficult to compare and hinder the use of this model for therapeutic development. We provide the most detailed active MOG35–55-EAE protocol to date. With this protocol, we observe high disease incidence and a consistent, reliable disease course. The resulting pathology is MS-like and includes optic neuritis, perivascular mononuclear infiltration, CNS axon demyelination, and axon damage in both infiltrating lesions and otherwise normal-appearing white matter. Conclusions By providing a detailed active MOG35–55-EAE protocol that yields consistent and robust pathology, we aim to foster comparability between pre-clinical studies and facilitate the discovery of MS therapeutics.

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Viral models of multiple sclerosis: Neurodegeneration and demyelination in mice infected with Theiler's virus

Cited by 84 publications

References 236 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

Molecular dialogs between the ischemic brain and the peripheral immune system: Dualistic roles in injury and repair

Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair

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Viral models of multiple sclerosis: Neurodegeneration and demyelination in mice infected with Theiler's virus

Cited by 84 publications

References 236 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

Molecular dialogs between the ischemic brain and the peripheral immune system: Dualistic roles in injury and repair

Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair

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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