Targeting Repulsive Guidance Molecule A to Promote Regeneration and Neuroprotection in Multiple Sclerosis (original) (raw)
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Therapeutic strategies to prevent neurodegeneration and promote regeneration in multiple sclerosis
2005
Multiple sclerosis (MS) is an immune-mediated demyelinating and degenerative disease of the central nervous system (CNS), with lesions predominantly occurring in the CNS white matter. The current treatment for MS relies on therapies that primarily target the peripheral immune response. However, it is clear that these strategies alone are insufficient for treating the chronic progressive disability that is the ultimate outcome of the disease. Axonal degeneration may be the primary determinant of fixed neurological deficits in MS. Here, we will discuss the contribution of axonal damage to MS pathogenesis, and potential cellular and molecular targets in the prevention of neurodegeneration. In addition, we will discuss potential molecular approaches to promote repair of CNS components in multiple sclerosis.
Multiple sclerosis: a battle between destruction and repair
Journal of Neurochemistry, 2007
Multiple sclerosis (MS) is a chronic neurodegenerative disease of the CNS in which an unrelenting attack from the innate and adaptive arms of the immune system results in extensive demyelination, loss of oligodendrocytes and axonal degeneration. This review summarizes advances in the understanding of the cellular and molecular pathways involved in neurodegeneration following autoimmune-mediated inflammation in the CNS. The mechanisms underlying myelin and axonal destruction and the equally important interaction between degenerative and repair mechanisms are discussed. Recent studies have revealed that the failure of CNS regeneration may be in part a result of the presence of myelin-associated growth inhibitory molecules in MS lesions. Successful therapeutic intervention in MS is likely to require suppression of the inflammatory response, in concert with blockade of growth inhibitory molecules and possibly the mobilization or transplantation of stem cells for regeneration.
Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis
Journal of Clinical Investigation, 2008
-75-treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases. Nonstandard abbreviations used: GS, glutamine synthetase; LDH, lactate dehydrogenase; MOG, myelin-oligodendrocyte glycoprotein; RR-MS, relapsing-remitting MS; SP-MS, secondary progressive MS.
Novel Therapeutic Targets for Axonal Degeneration in Multiple Sclerosis
Journal of Neuropathology and Experimental Neurology, 2010
Multiple sclerosis (MS) is a devastating neurological condition that mainly affects young adults and is associated with long-standing morbidity. The pathophysiology of MS is believed to involve immune-mediated multifocal lesions in the CNS that are characterized by inflammation, demyelination, and axonal injury. Most research efforts to date have concentrated on the mechanisms of immune-mediated demyelination, whereas mechanisms of axonal injury, the major determinant of neurological deficits in MS patients, have been elusive beyond observational analyses. This review discusses current understanding of the pathology and novel clinical investigations of axonal injury in MS and the commonly used MS animal model, experimental autoimmune encephalomyelitis. The review focuses on the etiology and the induction of axonal degeneration through molecular signaling cascades downstream of myelinassociated inhibitory factors. Defining and eventually elucidating the signaling pathways elicited during the onset and progression of MS may provide novel therapeutic strategies to limit axonal degeneration in the acute phase of the disease. Furthermore, blocking or potentiating specific signaling pathways, particularly those that mediate axon retraction and promote disassembly of the tubulin network, may promote regrowth of damaged axons in CNS regions affected by many acute and chronic disease processes.
Neuroprotection: A New Therapeutic Approach of Relapsing Remitting Multiple Sclerosis
Trending Topics in Multiple Sclerosis, 2016
Neurodegenerative changes occurring early from primary acute immune-mediated inflammation support the hypothesis that multiple sclerosis (MS) is a complex disease. Axonal loss progresses with the disease course and represents the principal driver of disability. In this context, the pursuit of neuroprotective therapies in multiple sclerosis provides new valid alternatives that could significantly impact on disease progression and neurodegenerative changes, including the promotion of restoration of myelin sheaths through the remyelination process. This chapter reviews promising drugs with proposed neuroprotective or neuroregenerative effects that are currently approved or in clinical trials for the treatment of multiple sclerosis. Although the chapter highlights the diazoxide action on neuroinflammation and the results of a clinical trial with this drug, the review also includes other molecules with oral or parenteral administration.
Mechanisms of tissue injury in multiple sclerosis: opportunities for neuroprotective therapy
Advances in Research on Neurodegeneration, 2000
Development of neuroprotective therapies for multiple sclerosis is dependent on defining the precise mechanisms whereby immune effector cells and molecules are able to induce relatively selective injury of oligodendrocytes (OLs) and their myelin membranes. The selectivity of this injury could be conferred either by the properties of the effectors or the targets. The former would involve antigen specific recognition by either antibody or T cell receptor of the adaptive immune system. OLs are also susceptible to non antigen restricted injury mediated by components of the innate immune system including macrophages/microglia and NK cells. Target related selectivity could reflect the expression of death inducing surface receptors (such as Fas or TNFR-l) required for interaction with effector mediators and subsequent intracellular signaling pathways, including the caspase cascade. Development of therapeutic delivery systems, which would reach the site of disease activity within the eNS, will permit the administration of inhibitors either of the cell death pathway or of effector target interaction and opens new avenues to neuroprotection approach.
Multiple Sclerosis: From Molecules to Treatment
International Journal of Molecular Sciences, 2013
The treatment of multiple sclerosis has been radically transformed over the past 20 years and this special issue of IJMS, focusing on the molecular aspects of the disease, highlights the growing conformity of the various investigative approaches. It is a very exciting time to be involved in the research of this disease.
Journal of Experimental and Clinical Neurosciences, 2014
Even though steroids have drawn significant therapeutic interests for decades, data about their benefits for neural regeneration are missing as current observational studies unfold progressive abnormalities in cerebral gray matter and cerebellum compartments, apart from demyelination lesions in white matter of the central nervous system (CNS) in multiple sclerosis (MS). This medical-scientific appraisal is based on a series of structured questions in part addressed in our investigative clinical review on the benefits and risks of glucocorticosteroids (GC), which highlights that steroids can intensify the disease progression, aside from other global side effects recognized in MS and associated optic neuritis (MS-ON). Corticosteroids treatments, whilst temporally and selectively suppress immune reactions, can interfere with the clearance of myelin debris and inhibit proliferation-migration of the myelinating cells, affecting the axonal repair and CNS functions. This review compiles and summarizes datasets extracted largely from complementary laboratory studies published in Medline, It discusses related pharmacologic and disease mechanisms and relevancies of the distinct MS disease models in rodents, with emphasis on the strengths and weaknesses of the associations of GCs use, glucocorticoid receptors sensitivity, and clinical outcomes. Based on these assessments, we conclude that steroids can suppress inflammation to the determent of neuronal remodeling in a mutually exclusive manner. Excess steroids can contribute to neuronal loss and retinal damage in optic pathology, and thus may expand cerebral atrophy and disease burden in multiple sclerosis.
Neuron, 2003
Neurological 3-to 4-fold risk for MS. Other genes within the HLA Sciences complex, including tumor necrosis factor (TNF)-␣, com-Beckman Center for Molecular Medicine ponents of the complement cascade, and myelin oligo-Stanford University dendrocyte glycoprotein (MOG), are also involved in MS Stanford, California 94305 pathogenesis. However, genes outside the HLA complex also contribute to MS pathogenesis. In fact, genome-based studies of multiplex MS families (more than Multiple sclerosis (MS) is an autoimmune central nerone family member affected) indicate that 10 to 15 chovous system (CNS) demyelinating disease that causes mosomal loci contribute to MS susceptibility. Multiple relapsing and chronic neurologic impairment. Recent genes acting in concert may elevate the risk for MS. observations have altered certain traditional concepts Myelin-Specific CD4 ؉ T Cells Initiate regarding MS pathogenesis. A greater diversity of cell CNS Inflammation types and molecules involved in MS is now evident.
Journal of Neuroinflammation, 2015
Background: Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in chronic demyelinating disease with progressive axonal loss and neurologic dysfunction similar to progressive forms of multiple sclerosis (MS). We previously showed that as the disease progresses, a marked decrease in brainstem N-acetyl aspartate (NAA; metabolite associated with neuronal integrity) concentrations, reflecting axon health, is measured. We also demonstrated stimulation of neurite outgrowth by a neuron-binding natural human antibody, IgM12. Treatment with either the serum-derived or recombinant human immunoglobulin M 12 (HIgM12) preserved functional motor activity in the TMEV model. In this study, we examined IgM-mediated changes in brainstem NAA concentrations and central nervous system (CNS) pathology.