Insights Into the Molecular Pathogenesis of Progression in Multiple Sclerosis

Imitola, Jaime; Chitnis, Tanuja; Khoury, Samia J.

doi:10.1001/archneur.63.1.25

Cited by 78 publications

(64 citation statements)

References 83 publications

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“…However, these generalizations remain controversial and variable depending on the cytokines, cell-types, and inflammatory conditions that are involved, as discussed in detail in many excellent reviews [11][12][13][14][15][16]. There is no doubt, however, that inflammation is linked to many diseases of the nervous system [17][18][19].…”

Section: Inflammation and Migration: Regulation By Gsk3mentioning

confidence: 99%

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

2006

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Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer's disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.

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Section: Inflammation and Migration: Regulation By Gsk3mentioning

confidence: 99%

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

2006

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“…Over time, permanent neurologic disability accrues as a result of the uncontrolled activation of inflammatory and degenerative pathways within the CNS (2)(3)(4). Identifying mediators that govern these pathways is critical for the development of successful new therapeutics to prevent disease progression.…”

Section: Ultiple Sclerosis (Ms) Is a Progressive Immune-mediated Dementioning

confidence: 99%

Macrophage Migration Inhibitory Factor Potentiates Autoimmune-Mediated Neuroinflammation

Cox

Kithcart

Pitt

et al. 2013

The Journal of Immunology

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Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that is associated with clinical worsening and relapses in multiple sclerosis (MS) patients. The mechanism through which MIF promotes MS progression remains undefined. In this study, we identify a critical role for MIF in regulating CNS effector mechanisms necessary for the development of inflammatory pathology in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Despite the ability to generate pathogenic myelin-specific immune responses peripherally, MIF-deficient mice have reduced EAE severity and exhibit less CNS inflammatory pathology, with a greater percentage of resting microglia and fewer infiltrating inflammatory macrophages. We demonstrate that MIF is essential for promoting microglial activation and production of the innate soluble mediators IL-1β, IL-6, TNF-α, and inducible NO synthase. We propose a novel role for MIF in inducing microglial C/EBP-β, a transcription factor shown to regulate myeloid cell function and play an important role in neuroinflammation. Intraspinal stereotaxic microinjection of MIF resulted in upregulation of inflammatory mediators in microglia, which was sufficient to restore EAE-mediated inflammatory pathology in MIF-deficient mice. To further implicate a role for MIF, we show that MIF is highly expressed in human active MS lesions. Thus, these results illustrate the ability of MIF to influence the CNS cellular and molecular inflammatory milieu during EAE and point to the therapeutic potential of targeting MIF in MS.

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“…26 This was a prospective, open-label, baseline-controlled study conducted in 10 patients with relapsingremitting MS. The study comprised four phases: a six-week baseline phase, an 18-week treatment phase (weeks 0-18), a four-week washout phase (weeks [19][20][21][22], followed by a second 48-week treatment phase (weeks . At the beginning of each treatment phase, the dose of FAE treatment was titrated over nine weeks up to a dose of 240mg (120mg tablets) three times/day (TID), administered by mouth (PO) during the first treatment phase, and up to 120mg TID PO during the second treatment phase.…”

Section: Clinical Efficacy and Safetymentioning

confidence: 99%

“…19,20 In addition, there is accumulating scientific evidence that oxidative stress may play a major role in the neuronal damage that occurs in MS. 21 For example, activated macrophages and microglial cells may degrade myelin and damage oligodendrocytes by generating oxygen or nitrogen free radicals, producing excitatory amino acids and releasing proteolytic and lipolytic enzymes. 22 FAEs have been shown to affect aspects of the inflammatory cascade thought to be involved in MS. Data from in vitro studies showed that dimethyl fumarate and related FAEs increase the production and induce the expression of anti-inflammatory cytokines, such as interleukin (IL)-10, IL-4 and IL-5. [23][24][25][26] Other in vitro studies demonstrated that dimethyl fumarate and its primary metabolite, monomethyl fumarate, can both inhibit expression of proinflammatory cytokines such as IL-6, IL-1β and tumour necrosis factor (TNF)-α and inhibit the secondary effects of inflammatory cytokines such as IL-1β and TNF-α.…”

mentioning

confidence: 99%

BG00012 - A Novel Oral Therapy in Development for the Treatment of Multiple Sclerosis

Fox¹,

Neurologist²

2008

European Neurological Review

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Multiple sclerosis (MS) is an inflammatory disease of the brain and spinal cord characterised by focal areas of demyelination and neuronal destruction. Historically, disease-modifying therapies used to treat MS have been administered by injection, exerting their effects through generalised immunomodulatory and anti-inflammatory mechanisms. 1 These injection therapies are only moderately effective in reducing relapses and disability progression, 2-5 and many patients discontinue therapy due to tolerability concerns, fear and/or inconvenience of frequent injections. 6,7 Thus, there is an unmet medical need in MS for safe and effective oral therapies with novel mechanisms of action. This article discusses the potential mechanisms of action of BG00012 and reviews the available clinical data of its efficacy and safety in patients with MS. In addition, two phase III clinical trials of BG00012 in patients with relapsing-remitting MS that are currently recruiting patients are described. Potential Mechanisms of Action in Multiple SclerosisMS is an autoimmune-mediated disorder characterised by inflammation, destruction of myelin, loss of oligodendrocytes, axonal damage and subsequent neuronal loss in the central nervous system (CNS). [13][14][15][16] Although the pathogenesis of MS is not completely understood, In addition to exerting anti-inflammatory effects, BG00012 may modulate metabolic homeostasis and cellular response to oxidative stress, a possible cause of cell and tissue damage in persistent inflammation (see Figure 1). Dimethyl fumarate is a well-known inducer of phase II detoxification genes, and treatment of cultured astroglia and microglia with FAEs has been shown to upregulate the Phase II detoxification enzyme NAD(P)H:quinone oxidoreductase-1 (NQO-1). 30 The NQO-1 gene is a prototypical transcriptional target for the nuclear factor E2-related factor 2 (Nrf2), a transcription factor that controls Phase II detoxifying gene expression and is critical for oxidative stress response and immune homeostasis. 31,33,34 Recent studies have demonstrated that BG00012 and monomethyl fumarate can activate Nrf2 in vitro. 35 The Nrf2 pathway has been implicated as a mediator of a range of neuroprotective effects in the CNS, including inhibition of oxidative and excitotoxic neuronal damage, [36][37][38][39][40] protection of the BBB 41 and regulation of myelin maintenance. 42 Hence, the current body of experimental evidence suggests that BG00012 may provide a dual neuroprotective and anti-inflammatory a report by

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Insights Into the Molecular Pathogenesis of Progression in Multiple Sclerosis

Cited by 78 publications

References 83 publications

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

Macrophage Migration Inhibitory Factor Potentiates Autoimmune-Mediated Neuroinflammation

BG00012 - A Novel Oral Therapy in Development for the Treatment of Multiple Sclerosis

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