Retinoid X receptor gamma signaling accelerates CNS remyelination

Huang, Jeffrey K.; Jarjour, Andrew A.; Oumesmar, Brahim Nait; Kerninon, Christophe; Williams, Anna; Krężel, Wojciech; Kagechika, Hiroyuki; Bauer, Julien; Zhao, Chao; Evercooren, Anne Baron-Van; Chambon, Pierre; ffrench‐Constant, Charles; Franklin, Robin J.M.

doi:10.1038/nn.2702

Cited by 462 publications

(509 citation statements)

References 41 publications

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“…RXRγ was recently identified as a factor regulating myelination in a microarray analysis of separate stages of spontaneous remyelination after focal demyelination in the rat CNS [28] . RXRγ is highly expressed in remyelinating lesions, suggesting that it may be important in lesion repair.…”

Section: Retinoid X Receptor-gammamentioning

confidence: 99%

“…This was further investigated by gain/loss-of-function studies in purified OPC and cerebellar slice cultures. Knockdown of RXRγ by RNA interference or RXR-specific antagonists severely inhibits oligodendrocyte differentiation in culture, while the RXR agonist 9-cis-retinoic acid promotes remyelination in demyelinated cerebellar slice cultures and in demyelinated aged rats [28] . However, given the pleiotropic roles of RXRγ and its diverse partners, a general RXRγ agonist may have significant side effects.…”

Section: Retinoid X Receptor-gammamentioning

confidence: 99%

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Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Zhang

Guo

2013

Neurosci. Bull.

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Multiple sclerosis (MS) is a chronic and devastating autoimmune demyelinating disease of the central nervous system. With the increased understanding of the pathophysiology of this disease in the past two decades, many disease-modifying therapies that primarily target adaptive immunity have been shown to prevent exacerbations and new lesions in patients with relapsing-remitting MS. However, these therapies only have limited efficacy on the progression of disability. Increasing evidence has pointed to innate immunity, axonal damage and neuronal loss as important contributors to disease progression. Remyelination of denuded axons is considered an effective way to protect neurons from damage and to restore neuronal function. The identification of several key molecules and pathways controlling the differentiation of oligodendrocyte progenitor cells and myelination has yielded clues for the development of drug candidates that directly target remyelination and neuroprotection. The long-term efficacy of this strategy remains to be evaluated in clinical trials. Here, we provide an overview of current and emerging therapeutic concepts, with a focus on the opportunities and challenges for the remyelination approach to the treatment of MS.

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Section: Retinoid X Receptor-gammamentioning

confidence: 99%

Section: Retinoid X Receptor-gammamentioning

confidence: 99%

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Zhang

Guo

2013

Neurosci. Bull.

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“…Analysis of gene expression profiles during development in the normal adult brain and during demyelination identified several novel regulatory pathways of oligodendrocyte differentiation. These studies showed that oligodendrocyte differentiation and remyelination are dependent on retinoid-X receptor-gamma receptor agonists [115] and on Wnt-beta-catenin signaling [116]. In addition, type 2 cyclin dependent kinase (also known as cdk2), which controls the cell cycle, does not interfere with myelination during development, but its knock-out facilitates remyelination [117].…”

Section: Myelin Regeneration Fails In Msmentioning

confidence: 99%

Cell Therapy for Multiple Sclerosis

Ben‐Hur

2011

Neurotherapeutics

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The spontaneous recovery observed in the early stages of multiple sclerosis (MS) is substituted with a later progressive course and failure of endogenous processes of repair and remyelination. Although this is the basic rationale for cell therapy, it is not clear yet to what degree the MS brain is amenable for repair and whether cell therapy has an advantage in comparison to other strategies to enhance endogenous remyelination. Central to the promise of stem cell therapy is the therapeutic plasticity, by which neural precursors can replace damaged oligodendrocytes and myelin, and also effectively attenuate the autoimmune process in a local, nonsystemic manner to protect brain cells from further injury, as well as facilitate the intrinsic capacity of the brain for recovery. These fundamental immunomodulatory and neurotrophic properties are shared by stem cells of different sources. By using different routes of delivery, cells may target both affected white matter tracts and the perivascular niche where the trafficking of immune cells occur. It is unclear yet whether the therapeutic properties of transplanted cells are maintained with the duration of time. The application of neural stem cell therapy (derived from fetal brain or from human embryonic stem cells) will be realized once their purification, mass generation, and safety are guaranteed. However, previous clinical experience with bone marrow stromal (mesenchymal) stem cells and the relative easy expansion of autologous cells have opened the way to their experimental application in MS. An initial clinical trial has established the probable safety of their intravenous and intrathecal delivery. Short-term follow-up observed immunomodulatory effects and clinical benefit justifying further clinical trials.

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“…Recent reports suggest that demyelination in experimental allergic encephalomyelitis (EAE) is related to an increase in ApoE 25, which supports the present findings. In addition, retinoid acids (rxrs) are essential for cholesterol metabolism 27, 28 and stimulate oligodendrocyte differentiation 29. Interestingly, we found that 0.5 mg/kg of WIN during CPZ exposure increased the expression of Rxra which might protect myelinated axons against cuprizone.…”

Section: Discussionmentioning

confidence: 86%

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone‐Induced Central Nervous System Demyelination

et al. 2016

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SummaryAim and methodsDifferent types of insults to the CNS lead to axon demyelination. Remyelination occurs when the CNS attempts to recover from myelin loss and requires the activation of oligodendrocyte precursor cells. With the rationale that CB1 receptor is expressed in oligodendrocytes and marijuana consumption alters CNS myelination, we study the effects of the cannabinoid agonist WIN55212.2 in (1) an in vitro model of oligodendrocyte differentiation and (2) the cuprizone model for demyelination.ResultsThe synthetic cannabinoid agonist WIN55212.2 at 1 μM increased the myelin basic protein mRNA and protein expression in vitro. During cuprizone‐induced acute demyelination, the administration of 0.5 mg/kg WIN55212.2 confers more myelinated axons, increased the expression of retinoid X receptor alpha, and declined nogo receptor expression. Controversially, 1 mg/kg of the drug increased the number of demyelinated axons and reduced the expression of nerve growth factor inducible, calreticulin and myelin‐related genes coupling specifically with a decrease in 2′,3′‐cyclic nucleotide 3′ phosphodiesterase expression.ConclusionThe cannabinoid agonist WIN55212.2 promotes oligodendrocyte differentiation in vitro. Moreover, 0.5 mg/kg of the drug confers neuroprotection during cuprizone‐induced demyelination, while 1 mg/kg aggravates the demyelination process.

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Retinoid X receptor gamma signaling accelerates CNS remyelination

Cited by 462 publications

References 41 publications

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Promoting remyelination for the treatment of multiple sclerosis: opportunities and challenges

Cell Therapy for Multiple Sclerosis

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone‐Induced Central Nervous System Demyelination

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