Promoting remyelination in multiple sclerosis: Current drugs and future prospects

Abstract

Multiple sclerosis (MS)-a disease with remyelination failure MS, first described by Jean-Martin Charcot almost 150 years ago, 1 is a chronic inflammatory disease of the central nervous system (CNS). As tissue damage in MS was solely considered to be the result of an autoimmune inflammatory CNS process, it is hardly surprising that therapies developed over the course of the last 20 years have mainly focused on the immune system and, more specifically, on the modulation of immune cell behavior. Even though the currently available MS drugs are reliable, constantly improving, 2 very effective in MS with relapses, and able to significantly reduce long-term disability in MS patients, 3 they have only a limited effect on the progressive disease course without additional inflammatory relapses. 4 As neuroarchitectural damage caused during disease relapses accumulates over time and results in increasing patient disability, it is critical to develop new therapies aiming at the regenerative mechanisms of MS pathogenesis.Neurological disability during relapsing-remitting multiple sclerosis (RRMS) occurs in reversible episodes driven primarily by focal inflammatory demyelination, which destroys myelin, myelin-forming cells (oligodendrocytes), and axons. 5 Untreated relapses usually last no more than a few months, after which the patient typically regains neurological function. Remyelination, accompanied by resolution of the inflammation and reorganization of axonal sodium channels on demyelinated axons, helps restore axonal conduction and contributes to the clinical recovery or remission. 6 This remyelination during early disease is extensive in some MS patients but declines during the progressive disease course. 7,8 During this progressive phase of the disease, where acute inflammatory relapses are scarce with increasing loss of neuronal function, exogenous stimulation of endogenous remyelination would potentially have the greatest impact. Oligodendroglial precursor cells (OPCs) as a source for remyelinationCurrent research on the treatment of MS is directed at three major goals: preventing the development of new demyelinating lesions, protecting demyelinated axons from degeneration, and promoting remyelination. Phases of remyelination occur frequently during the RRMS disease course and are probably most relevant Promoting remyelination in multiple sclerosis: Current drugs and future prospects David Kremer, Patrick Küry and Ranjan DuttaAbstract: Myelin destruction due to inflammatory oligodendrocyte cell damage or death in conjunction with axonal degeneration are among the major histopathological hallmarks of multiple sclerosis (MS). The majority of available immunomodulatory medications for MS are approved for relapsing-remitting (RR) MS, for which they reduce relapse rate, MRI measures of inflammation, and the accumulation of disability. These medications are, however, of little benefit during progressive MS where axonal degeneration following demyelination outweighs inflammation. This has sparked great interest in the dev...

Depletion of Olig2 in oligodendrocyte progenitor cells infected by Theiler’s murine encephalomyelitis virus

“…Identification of genes that contribute to OPC proliferation and differentiation is of great interest, particularly in the treatment of multiple sclerosis, where remyelination is limited and declines during the progressive stage of disease (Boulanger and Messier 2014;Hauser et al 2013;Kremer et al 2015). Spontaneous remyelination in TMEV-IDD is observed infrequently in a small fraction of lesions (Denic et al 2014;Pirko et al 2004).…”

White Matter Dementia: Origin, Development, Progress, and Prospects

“…48 Stimulation of oligodendrocytes to enhance myelination with the neurotrophins nerve growth factor and brainderived neurotrophic factor has also been proposed, 48,49 and oligodendrocyte stimulation after ischemia has been observed with the use of many diverse agents such as aspirin, cerebrolysin, thymosin b4, and sildenafil. 50 The area of remyelination has long been studied by neurologists seeking to repair the effects of demyelination in MS and related diseases, and among many new ideas, remyelination is being studied with fingolimod (the first approved oral medication for MS), the anticholinergic drug benztropine, and an antibody against the transmembrane protein known as leucine-rich repeat and immunoglobulin domain-containing Nogo receptor interacting protein 51 . Stem cells may also have a role in restoring white matter after pathological insult, and strategies are being considered to mobilize oligodendrocyte precursor cells as a means of stimulating endogenous repair, and to deliver myelinogenic stem cells exogenously.…”

Thyroid Hormone Potentially Benefits Multiple Sclerosis via Facilitating Remyelination

“…Specifically, magnitude of myelin loss is proved to be positively correlated with microgliosis in the cuprizone model [5], and approximately 85 % of MS patients begins with a course of recurrent and reversible neurological deficits in the presence of focal inflammatory demyelination [6]. To rescue this deficiency, exogenous stimulation of endogenous remyelination, a regenerative process by which demyelinated axons are myelinated and neuronal function deficits are restored [7][8][9], would potentially have the greatest impact. Thyroid hormone (TH) plays a critical role in the central nervous system (CNS) development, regulating neuronal growth and synaptogenesis [10,11].…”