Targeting remyelination treatment for multiple sclerosis

Since disability in multiple sclerosis (MS) is a product of neurodegeneration and deficient remyelination, the ability to enhance neuroregeneration and myelin regeneration in MS is an enticing goal for MS drug development. In particular, remyelination treatments could promote return of neurological function and also prevent further axonal loss and neurodegeneration in MS due to trophic effects of myelin. The study of remyelination has advanced dramatically in the last several years such that a number of pathways inhibiting remyelination have been discovered, including those involving LINGO-1, Notch-1, hyaluronan, retinoid X receptor, and wnt/ß-catenin. Other approaches such as high throughput drug screening for remyelination drugs have caught fire, with identification of dozens of known drugs with oligodendrocyte maturation stimulatory effects. Several drugs identified through screens and other mechanisms are in the process of being further evaluated for remyelination in MS and MS models. We discuss the potential molecular targets and the variety of mechanisms towards drug identification and development in remyelination for MS.     

A monoclonal autoantibody which promotes central nervous system remyelination is highly polyreactive to multiple known and novel antigens

A monoclonal antibody (mAb), designated SCH94.03, which promotes central nervous system remyelination in susceptible mice infected with Theiler's virus, has been proposed to be a natural autoantibody based on its germline immunoglobulin sequence. To identify the potential antigens recognized by mAb SCH94.03, a rat brain λgt11 cDNA expression library was screened with this antibody. Nine independent clones were identified. Five clones were identical or highly similar to known cDNAs or proteins (rat kinesin light chain, mouse thrombospondin 1, mouse oncofetal antigen, RNA polymerase beta subunit and nuclear phosphoprotein). Four clones, designated REM#1, REM#2, REM#3 and REM#4, contained open reading frames, but were not homologous to any known genes or proteins. The reactivity of SCH94.03 with all nine clones was specific in that all nine clones identified contained continuous open reading frames and none of nine control IgM mAbs showed reactivity with any of the nine cDNA clones. The precise specificity of binding of mAb SCH94.03 was demonstrated by the absence of reactivity to the identified clones with IgM Ab from B cell lymphoma (CH12) which has identical cDNA sequences with mAb SCH94.03, but differ only in the heavy chain CDR3 N region. Our studies support the hypothesis that highly polyreactive natural autoantibodies can play a role in promoting central nervous system remyelination.     

Inhibition of CXCR2 signaling promotes recovery in models of multiple sclerosis

Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination/remyelination episodes that ultimately fail. Chemokines and their receptors have been implicated in both myelination and remyelination failure. Chemokines regulate migration, proliferation and differentiation of immune and neural cells during development and pathology. Previous studies have demonstrated that the absence of the chemokine receptor CXCR2 results in both disruption of early oligodendrocyte development and long-term structural alterations in myelination. Histological studies suggest that CXCL1, the primary ligand for CXCR2, is upregulated around the peripheral areas of demyelination suggesting that this receptor/ligand combination modulates responses to injury. Here we show that in focal LPC-induced demyelinating lesions, localized inhibition of CXCR2 signaling reduced lesion size and enhanced remyelination while systemic treatments were relatively less effective. Treatment of spinal cord cultures with CXCR2 antagonists reduced CXCL1 induced A2B5+ cell proliferation and increased differentiation of myelin producing cells. More critically, treatment of myelin oligodendrocyte glycoprotein peptide 35–55-induced EAE mice, an animal model of multiple sclerosis, with small molecule antagonists against CXCR2 results in increased functionality, decreased lesion load, and enhanced remyelination. Our findings demonstrate the importance of antagonizing CXCR2 in enhancing myelin repair by reducing lesion load and functionality in models of multiple sclerosis and thus providing a therapeutic target for demyelinating diseases.     

New ex vivo demyelination/remyelination models to defeat multiple sclerosis and neuromyelitis optica

<正>Multiple sclerosis(MS)and neuromyelitis optica(NMO)are inflammatory diseases of the central nervous system(CNS)resulting in CNS inflammation,infiltration of peripheral immune cells,loss of myelin and oligodendrocytes,interruption of axonal communication,and neurologic deficits.Following oligodendrocyte injury,     

Osteopontin is extensively expressed by macrophages following CNS demyelination but has a redundant role in remyelination

Osteopontin (OPN) is a key immunoregulator in the autoimmune-mediated demyelinating disease multiple sclerosis. OPN may also play a role in the remyelination since it is 1) a ligand for αV integrins, several of which regulate the properties of the oligodendrocyte precursor cells (OPCs) primarily responsible for remyelination, and 2) enhances myelin membrane formation in OPC lines. Here we show that OPN is expressed at high levels during remyelination of toxin-induced demyelination. The increased expression is due to mRNA expression in macrophages and follows differences in macrophage responses to demyelination in young and old adult animals. To identify the role of OPN in remyelination focal demyelination was induced in wild-type and OPN^−/− mice. There was no difference in the rate of remyelination between the two groups indicating that OPN is not a critical component of remyelination.     

BLBP-expression in astrocytes during experimental demyelination and in human multiple sclerosis lesions

Several lines of evidence indicate that remyelination represents one of the most effective mechanisms to achieve axonal protection. For reasons that are not yet understood, this process is often incomplete or fails in multiple sclerosis (MS). Activated astrocytes appear to be able to boost or inhibit endogenous repair processes. A better understanding of remyelination in MS and possible reasons for its failure is needed.Using the well-established toxic demyelination cuprizone model, we created lesions with either robust or impaired endogenous remyelination capacity. Lesions were analyzed for mRNA expression levels by Affymetrix GeneChip® arrays. One finding was the predominance of immune and stress response factors in the group of genes which were classified as remyelination-supporting factors. We further demonstrate that lesions with impaired remyelination capacity show weak expression of the radial-glia cell marker brain lipid binding protein (BLBP, also called B-FABP or FABP7). The expression of BLBP in activated astrocytes correlates with the presence of oligodendrocyte progenitor cells. BLBP-expressing astrocytes are also detected in experimental autoimmune encephalomyelitis during the remission phase. Furthermore, highest numbers of BLBP-expressing astrocytes were evident in lesions of early MS, whereas significantly less are present at the rim of (chronic)-active lesions from patients with long disease duration. Transfection experiments show that BLBP regulates growth factor expression in U87 astrocytoma cells. In conclusion, we provide evidence that expression of BLBP in activated astrocytes negatively correlates with disease duration and in parallel with remyelination failure.     

Central nervous system B-cell lymphoma in multiple sclerosis

The differential diagnosis of multiple sclerosis is extensive and it can be challenging to diagnose initially in the absence of pathognomonic clinical features. Furthermore, these patients can also develop other diseases during their course of treatment, which usually lasts for many years. Some conditions, such as primary central nervous system lymphoma, can mimic clinically some of the symptoms prominent in multiple sclerosis. Early treatment with corticosteroids can also dramatically improve patient symptoms in both conditions. We report a case of a man diagnosed with histologically confirmed relapsing remitting multiple sclerosis who subsequently developed histologically confirmed primary central nervous system lymphoma. The course of his disease and treatment are presented and the current literature reviewed.     

Overcoming remyelination failure in multiple sclerosis and other myelin disorders

Protecting axons from degeneration represents a major unmet need in the treatment of myelin disorders and especially the currently untreatable secondary progressive stages of multiple sclerosis (MS). Several lines of evidence indicate that ensuring myelin sheaths are restored to demyelinated axons, the regenerative process of remyelination, represents one of the most effective means of achieving axonal protection. Remyelination can occur as a highly effective spontaneous regenerative process following demyelination. However, for reasons that have not been fully understood, this process is often incomplete or fails in MS. Recognizing the reasons for remyelination failure and hence identifying therapeutic targets will depend on detailed histopathological studies of myelin disorders and a detailed understanding of the molecular mechanisms regulating remyelination. Pathology studies have revealed that chronically demyelinated lesions in MS often fail to repair because of a failure of differentiation of the precursor cell responsible for remyelination rather than a failure of their recruitment. In this article we review three mechanisms by which differentiation of precursor cells into remyelinating oligodendrocytes are regulated-the Notch pathway, the Wnt pathway and the pathways activated by inhibitor of differentiation in myelin debris-and indicate how these might be pharmacologically targeted to overcome remyelination failure.     

Spontaneous central nervous system remyelination in strain A mice after infection with the Daniel’s (DA) strain of Theiler’s virus

Intracerebral infection of susceptible SJL/J (H-2^s) mice with the Daniel’s strain of Theiler’s murine encephalomyelitis virus produces chronic, progressive, inflammatory central nervous system demyelination, with minimal spontaneous remyelination. To assess the role of host genetic factors in spontaneous myelin repair following chronic infection with the Daniel’s strain of Theiler’s virus, we examined demyelination and spontaneous remyelination in strain A mice after infection with Theiler’s virus. We found that A.BY/SnJ (H-2^b) mice were resistant to Theiler’s virus-induced demyelination, whereas A/J (H-2^a), A/WySnJ (H-2^a), and A.SW/SnJ (H-2^s) mice all developed chronic demyelination with substantial spontaneous remyelination 90 days after infection. In the spinal cords of both A/J and A/WySnJ mice, one quarter of the total lesion area showed spontaneous remyelination, whereas in A.SW/SnJ mice, the extent of remyelination increased to two thirds of the total lesion area. The spontaneous remyelination seen in strain A mice was consistent with myelin repair by oligodendrocytes and Schwann cells, and occurred despite the presence of persistent virus antigen. These results indicate that host-pathogen interactions play an important role in myelin regeneration after virus-induced demyelination, and suggest that host genetic factors influence spontaneous remyelination. Received: 3 October 1995 / Revised, accepted: 28 November 1995     

Vitamin B12, demyelination, remyelination and repair in multiple sclerosis

Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.     

Expression pattern of NOGO-A protein in the human nervous system

The distribution pattern of NOGO-A protein, an important axon growth inhibitory molecule and member of the reticulon family, has been investigated in the adult human brain, spinal cord, retina and dorsal root ganglia. Intense NOGO-A immunoreactivity was detected in oligodendroglial cell bodies and their myelin sheaths in nerve fibre tracts of the central nervous system. Furthermore, numerous populations of neurons in the brain and spinal cord expressed NOGO-A to a variable extent in their cell bodies and neurites, suggesting additional, as-yet-unknown, functions of this protein.     

Axonal signals in central nervous system myelination, demyelination and remyelination

Axonal signals are key players in central nervous system myelination. During development, the onset of myelination depends on a balance between positive and negative axonal signals. Among negative signals are inhibitory adhesion molecules that need to be removed from the cell surface for the myelination process to proceed. Positive signals necessary to initiate myelination consist of both interactions with specific adhesion molecules and electrical activity-induced release of promyelinating factors. In multiple sclerosis, demyelination induces major modifications of axonal surface components. The disruption of these factors might participate to the failure of the myelin repair process.     

Thyroid hormone and remyelination in adult central nervous system: a lesson from an inflammatory-demyelinating disease

Re-myelination in the adult CNS has been demonstrated in different experimental models of demyelinating diseases. However, there is no clear evidence that re-myelination is effective in multiple sclerosis (MS), the most diffuse demyelinating disease. Moreover, chronic disabilities in MS are believed to be due to remyelination failure and consequent neuron damage and degeneration. Due to the presence of numerous oligodendrocyte precursors inside demyelination plaques, reasons for remyelination failure are unknown. In this paper, we reviewed data from embryonic development and in vitro studies supporting the primary role of thyroid hormone in oligodendrocyte maturation. We also reviewed personal data on the possibility of promoting myelination in chronic experimental allergic encephalomyelitis (EAE), a widely used experimental model of MS, by recruiting progenitors and channeling them into oligodendroglial lineage through the administration of thyroid hormone.     

Neuroimaging in postinfectious demyelination and nutritional disorders of the central nervous system

The myelin sheath and oligodendrocytes in the brain may be damaged by autoimmune-mediated inflammatory processes secondary to postinfectious demyelination or nutritional and vitamin deficiency. This article describes acute disseminated encephalomyelitis, acute hemorrhagic leukoencephalitis, acute necrotizing encephalopathy, and tumefactive demyelination as well as osmotic demyelination, Wernicke encephalopathy, Marchiafava-Bignami disease, and subacute combined degeneration of the spinal cord. Although some characteristic MR imaging features allow radiologists to suggest a diagnosis, these may overlap, and images should be interpreted in light of clinical symptoms and laboratory investigations.     

A differential diagnosis of central nervous system demyelination: beyond multiple sclerosis

Although multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system (CNS), it lacks any definitive diagnostic test. Instead, diagnosis of MS primarily depends upon clinical criteria, supported by abnormalities characteristic of MS on para-clinical investigations including magnetic resonance imaging of the brain and spine, in the absence of an alternative explanation for underlying neurologic symptoms. While many of the potential disorders that may mimic MS in routine clinical practice are either extremely rare, or associated with specific and characteristic distinguishing diagnostic features, some inflammatory demyelinating disorders of the CNS may be particularly challenging to distinguish from MS, especially during initial presentation. In particular, acute disseminated encephalomyelitis, neuromyelitis optica, and idiopathic transverse myelitis may closely resemble MS, impeding prompt and accurate diagnosis. In this review, we describe the clinical features, diagnosis, pathology, and treatment of these other CNS demyelinating disorders. In addition, we review relevant features of other CNS inflammatory disorders that may mimic MS, including Sj?gren's syndrome, systemic lupus erythematosus, Beh?et's disease, and primary CNS vasculitis.     

Neuronal gene transcription modulates demyelination and remyelination in a mouse model of multiple sclerosis

<正>The role of the neuronal compartment in multiple sclerosis:Multiple sclerosis(MS)is a chronic inflammatory demyelinating disease affecting the central nervous system(CNS).It is usually characterized by initial relapses and remissions with subsequent progressive neurological deterioration.MS is the most common acquired neurological disorder affecting young     

Corticosteroids delay remyelination of experimental demyelination in the rodent central nervous system

High dose corticosteroid (CS) administration is a common mode of therapy in treatment of acute relapses in multiple sclerosis (MS) but the effects of CS on remyelination and the cellular mechanisms mediating this repair process are controversial. We have examined CS effects on repair of toxin-induced demyelinating lesions in the adult rat spinal cord. Corticosteroids reduced the extent of oligodendrocyte remyelination at 1 month post lesion (whereas Schwann-cell mediated repair was unaffected). However, CS did not cause permanent impairment of remyelination as lesions were fully remyelinated at 2 months after cessation of treatment. The delay in oligodendrocyte mediated repair could be attributed to inhibition of differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes, with no effect of CS treatment observed on OPC colonisation of the lesions. No differences were observed in animals treated with methylprednisolone succinate alone or with a subsequent prednisone taper indicating that CS effects occur at an early stage of repair. The potential consequences of delayed remyelination in inflammatory lesions are discussed.     

Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide

Cannabinoids have recently been approved as a treatment for pain in multiple sclerosis (MS). Increasing evidence from animal studies suggests that this class of compounds could also prove efficient to fight neurodegeneration, demyelination, inflammation and autoimmune processes occurring in this pathology. However, the use of cannabinoids is limited by their psychoactive effects. In this context, potentiation of the endogenous cannabinoid signalling could represent a substitute to the use of exogenously administrated cannabinoid ligands. Here, we studied the expression of different elements of the endocannabinoid system in a chronic model of MS in mice. We first studied the expression of the two cannabinoid receptors, CB₁ and CB₂, as well as the putative intracellular cannabinoid receptor peroxisome proliferator-activated receptor-α. We observed an upregulation of CB₂, correlated to the production of proinflammatory cytokines, at 60 days after the onset of the MS model. At this time, the levels of the endocannabinoid, 2-arachidonoylglycerol, and of the anti-inflammatory anandamide congener, palmithoylethanolamide, were enhanced, without changes in the levels of anandamide. These changes were not due to differences in the expression of the degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase, or of biosynthetic enzymes, diacylglycerol lipase-α and N -acylphosphatidylethanolamine phospholipase-D at this time (60 days). Finally, the exogenous administration of palmitoylethanolamide resulted in a reduction of motor disability in the animals subjected to this model of MS, accompanied by an anti-inflammatory effect. This study overall highlights the potential therapeutic effects of endocannabinoids in MS.     

The demonstration of recurrent demyelination and remyelination of axons in the central nervous system

Summary A model for studying recurrent demyelination and remyelination in the central nervous system was developed by means of repeated administration of Cuprizone to mice. In contrast to the demyelination seen during the first course of Cuprizone, the recurrent demyelination was markedly protracted, displayed features of a dying-back gliopathy, and resulted in a greatly reduce inflammatory and glial reaction. The repeat remyelination also occurred at a slower tempo, varied markedly in completeness, and was associated with a diminished regeneration of oligodendrocytes. These results demonstrated that axons of the central nervous system in this model can be recurrently remyclinated if oligodendrocytes are available, that regeneration of oligodendrocytes is dependent upon the tissue reaction to demyelination, and that remyelinated axons are not more susceptible to demyelination than normal ones.