Thirteen compounds promoting oligodendrocyte progenitor cell differentiation and remyelination for treating multiple sclerosis: WO2010054307

Background: The application is in the field of cellular therapy and neural repair.

Objective: It aims at identifying and characterizing compounds and molecules that promote the differentiation of oligodendrocyte progenitor cells and remyelination of the nervous system.

Methods: Library of compounds and molecules were screened on a series of assays specifically designed and developed to assess the activity and potency of compounds and molecules on the differentiation of oligodendrocyte progenitor cells and on remyelination of nerve cells in in vitro and in vivo models, such as cultures of neural progenitor and stem cells, cerebellar organotypic cultures, the zebrafish and the cuprizone-mediated demyelination mouse models.

Results: In all, 13 compounds were identified and characterized, after a secondary screening, for inducing the differentiation of oligodendrocyte progenitor cells and for promoting myelination and remyelination in vitro and in vivo.

Conclusion: The 13 compounds, promoting the differentiation of oligodendrocyte progenitor cells and myelination of nerve cells, may be used for the treatment of multiple sclerosis (MS) and other myelin-related disorders. The application claims the use of the compounds to promote the differentiation of oligodendrocyte progenitor cells and endogenous remyelination for the treatment of demyelinating diseases alone or in combination with other agents and drugs, such as immunomodulatory, immunosuppressive, neuroprotective and neuroregenerative agents.     

Emerging molecular therapeutic targets for spinal cord injury

ABSTRACT

Introduction: Spinal cord injury (SCI) is a complicated and devastating neurological disorder. Patients with SCI usually have dramatically reduced quality of life. In recent years, numerous studies have reported advances in understanding the pathophysiology of SCI and developing preclinical therapeutic strategies for SCI, including various molecular therapies, and yet there is still no cure.

Areas covered: After SCI, tissue damage, responses and repair involve interactions among many cellular components, including neurons, axons, glia, leukocytes, and other cells. Accordingly, numerous cellular genes and molecules have become therapeutic targets for neural tissue repair, circuit reconstruction, and behavioral restoration. Here, we review the major recent advances in biological and molecular strategies to enhance neuroprotection, axon regeneration, remyelination, neuroplasticity and functional recovery in preclinical studies of SCI.

Expert opinion: Researchers have made tremendous progress in identifying individual and combined molecular therapies in animal studies. It is very important to identify additional highly effective treatments for early neuroprotective intervention and for functionally meaningful axon regeneration and neuronal reconnections. Because multiple mechanisms contribute to the functional loss after SCI, combining the most promising approaches that target different pathophysiological and molecular mechanisms should exhibit synergistic actions for maximal functional restoration. [Databases searched: PubMed; inclusive dates: 6/27/2019]     

Targeting oligodendrocyte protection and remyelination in multiple sclerosis

Multiple sclerosis is an inflammatory demyelinating disease of the brain and spinal cord with a presumed autoimmune etiology. Conduction block in demyelinated axons underlies early neurological symptoms, whereas axonal transection is believed responsible for more permanent later deficits. Approved treatments for the disease are immunoregulatory and reduce the rate of lesion formation and clinical exacerbation, but are only partially effective in preventing the onset of disability in multiple sclerosis patients. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination may improve long-term outcomes and reduce the rate of axonal transection. Studies in genetically modified animals have improved our understanding of mechanisms underlying central nervous system pathology in multiple sclerosis models, and have identified pathways that regulate oligodendrocyte viability and myelin repair. However, although clinical trials are ongoing, many have been unsuccessful, and no treatments are yet approved that target these areas in multiple sclerosis. In this review, we examine avenues for oligodendrocyte protection and endogenous myelin repair in animal models of demyelination and remyelination, and their relevance as therapeutics in human patients.     

Mechanisms Involved in the Remyelinating Effect of Sildenafil

Remyelination occurs in demyelinated lesions in multiple sclerosis (MS) and pharmacological treatments that enhance this process will critically impact the long term functional outcome in the disease. Sildenafil, a cyclic GMP (cGMP)-specific phosphodiesterase 5 inhibitor (PDE5-I), is an oral vasodilator drug extensively used in humans for treatment of erectile dysfunction and pulmonary arterial hypertension. PDE5 is expressed in central nervous system (CNS) neuronal and glial populations and in endothelial cells and numerous studies in rodent models of neurological disease have evidenced the neuroprotective potential of PDE5-Is. Using myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) as a MS model, we previously showed that daily administration of sildenafil starting at peak disease rapidly ameliorates clinical symptoms while administration at symptoms onset prevents disease progression. These beneficial effects of the drug involved down-regulation of adaptive and innate immune responses, protection of axons and oligodendrocytes (OLs) and promotion of remyelination. In this work we have investigated mechanisms involved in the remyelinating effect of sildenafil. Using demyelinated organotypic cerebellar slice cultures we demonstrate that sildenafil stimulates remyelination by direct effects on CNS cells in a nitric oxide (NO)-cGMP-protein kinase G (PKG)-dependent manner. We also show that sildenafil treatment enhances OL maturation and induces expression of the promyelinating factor ciliary neurotrophic factor (CNTF) in spinal cord of EAE mice and in cerebellar slice cultures. Furthermore, we demonstrate that sildenafil promotes a M2 phenotype in bone marrow derived macrophages (BMDM) and increases myelin phagocytosis in these cells and in M2 microglia/macrophages in the spinal cord of EAE mice. Taken together these data indicate that promotion of OL maturation directly or through induction of growth factor expression, regulation of microglia/macrophage inflammatory phenotype and clearance of myelin debris may be relevant mechanisms involved in sildenafil enhancement of remyelination in demyelinated tissue and further support the contention that this well tolerated drug could be useful for ameliorating MS pathology.     

Ibudilast for the treatment of multiple sclerosis

Introduction: Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) characterized by inflammatory demyelination and progressive axonal loss. Clinically, this is manifest as relapsing and remitting neurological symptoms and progressive accumulation of disability. Ibudilast is a nonselective phosphodiesterase inhibitor which works by blocking the cleavage of cyclic adenosine monophosphate (cAMP). It has been found to have anti-inflammatory and neuroprotective properties in animal studies and in-vitro studies; it is currently being studied in progressive MS.

Areas covered: This article reviews various studies looking at ibudilast as a potential therapy for MS. It summarizes prior and current clinical trials of ibudilast in MS as well as its pharmacology.

Expert opinion: Although ibudilast has not been found to decrease the focal inflammatory activity in relapsing MS, it was shown to have an effect on preserving brain volume and disability progression. Ibudilast may have a role in the treatment of progressive MS phenotypes.     

Roles of voltage-dependent sodium channels in neuronal development, pain, and neurodegeneration

Besides initiating and propagating action potentials in established neuronal circuits, voltage-dependent sodium channels sculpt and bolster the functional neuronal network from early in embryonic development through adulthood (e.g., differentiation of oligodendrocyte precursor cells into oligodendrocytes, myelinating axon; competition between neighboring equipotential neurites for development into a single axon; enhancing and opposing functional interactions with attractive and repulsive molecules for axon pathfinding; extending and retracting terminal arborization of axon for correct synapse formation; experience-driven cognition; neuronal survival; and remyelination of demyelinated axons). Surprisingly, different patterns of action potentials direct homeostasis-based epigenetic selection for neurotransmitter phenotype, thus excitability by sodium channels specifying expression of inhibitory neurotransmitters. Mechanisms for these pleiotropic effects of sodium channels include reciprocal interactions between neurons and glia via neurotransmitters, growth factors, and cytokines at synapses and axons. Sodium channelopathies causing pain (e.g., allodynia) and neurodegeneration (e.g., multiple sclerosis) derive from 1) electrophysiological disturbances by insults (e.g., ischemia/hypoxia, toxins, and antibodies); 2) loss-of-physiological function or gain-of-pathological function of mutant sodium channel proteins; 3) spatiotemporal inappropriate expression of normal sodium channel proteins; or 4) de-repressed expression of otherwise silent sodium channel genes. Na(v)1.7 proved to account for pain in human erythermalgia and inflammation, being the convincing molecular target of pain treatment.     

Treatment of walking impairment in multiple sclerosis: an unmet need for a disease-specific disability

Introduction: Walking impairment is a clinical hallmark of multiple sclerosis (MS), a chronic neurologic disease characterized by axonal demyelination and dysfunction that results in progressive disability. Until recently, there were no therapies that specifically targeted the axonal dysfunction associated with walking impairment in MS.

Areas covered: The purpose of this review is to discuss the unmet need for the treatment of walking impairment in MS patients and to evaluate how a new class of pharmacologic therapies, neurofunctional modifiers, potentially addresses this unmet need. Discussion is based on clinical experience and opinions supported by publications identified in the PubMed literature using the search terms ‘multiple sclerosis’ and ‘mobility OR walking’.

Expert opinion: The development and approval of new treatments for MS show promise for improving adherence to therapy and increasing the potential for clinical effectiveness. Renewed emphasis on integrating strategies that target the underlying pathophysiology with those that address symptoms of concern to patients also has the potential to improve the lives of MS patients and their caregivers. The introduction of neurofunctional modifiers, such as dalfampridine for the improvement of walking impairment, may be of benefit by improving function, mobility and overall quality of life for MS patients.     

Remyelinating and neuroprotective treatments in multiple sclerosis

Multiple sclerosis (MS) is the most common cause of neurological disability in young adults. The pathological hallmark is multifocal demyelination and inflammation in the CNS. In addition, there is also a variable extent of axonal damage. Remyelination has been seen in up to 70% of lesions but repair is generally incomplete. The demonstration of neuropathological heterogeneity of MS lesions suggests different pathophysiological subtypes and it is therefore unlikely that there is a uniform cause of incomplete remyelination in MS. In recent years, a great body of knowledge has accumulated in order to better understand the regulatory mechanisms of remyelination. This has led to a number of approaches to promote repair mechanisms, most of which have been successful in animal experiments. Unfortunately, the translation of these experimental data into clinical treatments has proven difficult. More information on the pathogenesis of MS, the reason why repair mechanisms fail in MS and a better understanding of the regulation of remyelination are required. This will ultimately lead to a specific treatment tailored for the individual patient and will probably involve a combination of immunomodulation, remyelination and neuroprotection.     

Promotion of remyelination by immunoglobulins: implications for the treatment of multiple sclerosis

During the last decade immunomodulatory treatments have been shown to influence the natural course of multiple sclerosis (MS). However, demyelination in the central nervous system (CNS) still occurs and repair mechanisms are incomplete leading to neurological deficits. Currently, there is no therapy available to promote remyelination and thus enhance repair mechanisms. Both immunoglobulins directed against spinal cord homogenate and polyclonal immunoglobulins for intravenous use (IVIg) have been shown to support remyelination in the animal model of Theiler's virus encephalomyelitis (TMEV). Further studies have identified monoclonal antibodies that lead to remyelination in TMEV and a toxic demyelination model using lysolecithin. The shared characteristics of these monoclonal antibodies are an IgM isotype and the capacity to bind oligodendrocytes, independent of epitope specificity. Recently, two human monoclonal antibodies with remyelinating properties were described. Clinical trials with IVIg have so far failed to demonstrate clinical improvement in MS patients, but these studies only employed IgG preparations. However, recent experimental data both in vivo and in vitro underline the importance of IgM for remyelination. Thus future clinical trials are needed to evaluate the remyelination potential of IgM in human diseases. The design of monoclonal antibodies capable of promoting remyelination is a telling example for the design of new specific therapies derived from biological products like polyclonal immunoglobulins.     

Remyelinating and neuroprotective treatments in multiple sclerosis

Multiple sclerosis (MS) is the most common cause of neurological disability in young adults. The pathological hallmark is multifocal demyelination and inflammation in the CNS. In addition, there is also a variable extent of axonal damage. Remyelination has been seen in up to 70% of lesions but repair is generally incomplete. The demonstration of neuropathological heterogeneity of MS lesions suggests different pathophysiological subtypes and it is therefore unlikely that there is a uniform cause of incomplete remyelination in MS. In recent years, a great body of knowledge has accumulated in order to better understand the regulatory mechanisms of remyelination. This has led to a number of approaches to promote repair mechanisms, most of which have been successful in animal experiments. Unfortunately, the translation of these experimental data into clinical treatments has proven difficult. More information on the pathogenesis of MS, the reason why repair mechanisms fail in MS and a better understanding of the regulation of remyelination are required. This will ultimately lead to a specific treatment tailored for the individual patient and will probably involve a combination of immunomodulation, remyelination and neuroprotection.     

Treatment of multiple sclerosis in children and adolescents

Importance of the field: Pediatric multiple sclerosis is an acquired inflammatory, demyelinating CNS disorder associated with recurrent episodes of neurologic dysfunction. Precise diagnosis is increasingly important as disease modifying therapies have been developed in adults and introduced into pediatric practice.

Areas covered in this review: Literature published over the past two decades relating to pharmacologic treatment of multiple sclerosis (MS) in adults and children is reviewed, with emphasis on current publications.

What the reader will gain: This article reviews available research and clinical experience regarding treatment of acute episodes of CNS demyelination in children and adolescents, strategies for introduction and modification of disease-modifying therapies depending on disease course, and use of medication for symptomatic improvement in quality of life.

Take home message: Pharmacotherapy for MS has been studied in adults but to a significantly lesser extent in children or adolescents. However, children and adolescents have different biology than adults in terms of drug metabolism, immune mechanisms and incomplete maturity of CNS myelin. Effectiveness as well as long-term safety needs to be studied in children and adolescents.     

The role of myelin oligodendrocyte glycoprotein in autoimmune demyelination: a target for multiple sclerosis therapy?

Introduction: Myelin oligodendrocyte glycoprotein (MOG) is a myelin antigen at the outer surface of the central nervous system (CNS) myelin sheath, which may trigger T-cell as well as B-cell responses. It therefore constitutes a pivotal target for autoimmune responses, which result in inflammation and also demyelination in the CNS. In particular, it is a major target for auto-antibodies in experimental autoimmune encephalomyelitis (EAE), which mimics many aspects of multiple sclerosis (MS). B-cell responses toward MOG and anti-MOG antibodies have also been demonstrated in patients with demyelinating diseases, such as MS and acute disseminating encephalomyelitis (ADEM). Co-transfer of such anti-MOG antibodies in experimental models results in a distinct lesion pattern with antibody and complement-mediated demyelination, which is also hallmark of some lesion subtypes in MS.

Areas covered: A comprehensive literature search on MOG, B cells, MS, and ADEM was performed to outline the role of MOG in autoimmune demyelination in animal models and its relevance for human disease.

Expert opinion: Although the definite role of MOG in the pathogenesis of MS still remains to be clarified, innovative therapeutic strategies targeting B cells may reduce pathogenic immune responses against myelin auto-antigens including anti-myelin auto-antibodies.     

Remyelinating strategies: What can be learned from normal brain development

Multiple sclerosis (MS) is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS). Immunomodulatory therapies are effective in reducing relapses, however, there is no remedy for progressive disease emphasizing the need for regenerative strategies. Chronic demyelination causes axonal injury and loss which is a key component of neurodegeneration and permanent disability in MS. New oligodendrocyte progenitor cells (OPCs) proliferate in response to inflammatory demyelination representing the potential for remyelination to protect axons and preserve neuronal function. The majority of remyelinating therapies have targeted intrinsic signaling processes in oligodendrocytes to promote differentiation or utilized methods for transplantation of oligodendrocytes. Here, we discuss specific roles of microglia in contributing to normal myelin development and the significance of these functions for remyelinating strategies.     

肿瘤坏死因子α在多发性硬化及髓鞘再生中的研究进展

肿瘤坏死因子（TNF-α）是一种多向性细胞因子,存在可溶性和跨膜两种形式,分别结合肿瘤坏死因子受体1（TNFR1）和TNFR2来发挥功能。近年来研究发现,TNF-α/TNFR通路在多发性硬化的发生和髓鞘再生中发挥了重要作用。TNFR1通过死亡受体介导凋亡信号通路,导致少突胶质细胞及神经元的凋亡,从而引起髓鞘脱失等神经退行性改变。TNFR2通过一系列级联反应促进少突胶质细胞前体细胞的增殖以及分化,从而促进髓鞘的再生,在多发性硬化中有积极作用。     

Siponimod for the treatment of secondary progressive multiple sclerosis

Introduction: Multiple sclerosis (MS) is a chronic central nervous system immune-mediated disease with an important inflammatory component associated with focal demyelination and widespread neurodegeneration. In most cases, the clinical presentation is relapsing-remitting, followed by a secondary progressive phase, characterized by disability accrual unrelated to relapses. In a minority, the phenotype is progressive from the beginning. Major therapeutic achievements have been made concerning the relapsing phase but modifying the evolution of progressive MS remains an unmet need.

Areas covered: This review covers siponimod (BAF312), a new sphingosine 1-phosphate receptor modulator, and its role in the treatment of secondary progressive MS. The authors reviewed PubMed English literature using the keywords ‘siponimod’ or ‘BAF312’ and ‘multiple sclerosis.’ They also present the pharmacological profile of siponimod, as well as clinical efficacy and safety, with emphasis on the recently published results of a Phase III trial. Phase II data in relapsing MS are also summarized.

Expert opinion: Siponimod may reduce the activity of the disease and has a modest effect on the gradual disability accrual. If approved, it may become one of the few available therapy options for secondary progressive MS.     

Mechanisms for dendritic morphogenesis of cerebellar purkinje cells: role of receptor-type protein tyrosine phosphatase zeta]

Cerebellar Purkinje cells have the most elaborate dendritic trees among neurons in the central nervous system, which are formed into a characteristic morphology during postnatal cerebellar development. PTPzeta is a receptor-type protein tyrosine phosphatase that is expressed predominantly in the central nervous system and synthesized as a chondroitin sulfate proteoglycan. PTPzeta and pleiotrophin, a ligand of PTPzeta, are distributed around Purkinje cell dendrites during postnatal cerebellar development. Our study using an organotypic slice culture system demonstrated that pleiotrophin-PTPzeta signaling is involved in the morphogenesis of Purkinje cell dendrites. An aberrant morphology of Purkinje cell dendrites such as multiple and disoriented primary dendrites was induced by disturbing pleiotrophin-PTPzeta signaling in slice cultures. Pleiotrophin-PTPzeta signaling appears to act on Bergmann glia and control formation and/or maintenance of GLAST-positive lamellate processes of Bergmann glia, which regulate the morphogenesis of Purkinje cell dendrites.     

The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination

BACKGROUND AND PURPOSE

Modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection.

EXPERIMENTAL APPROACH

In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin-induced experimental demyelination. We used histological, immunohistochemical and gene expression methods.

KEY RESULTS

The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone-induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this compound alleviated ongoing axonal damage.

CONCLUSIONS AND IMPLICATIONS

We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined.     

Natural products: Potential therapeutic agents in multiple sclerosis

Multiple sclerosis is an autoimmune neurodegenerative disease, which usually caused by inflammation, demyelination, and axonal injury. The currently available medications for multiple sclerosis do not directly promote myelin sheath repair. Therefore, many researches have attempted to achieve better therapeutic effects through promoting remyelination. Natural products not only alleviate clinical symptoms, but also have the unique advantages of protecting and repairing effects on nervous system. We here present a systematic review on published papers about treating multiple sclerosis by natural products, aiming to provide comprehensive information on natural products in the treatment of multiple sclerosis.     

Breaking the barriers to remyelination in multiple sclerosis

Chronically demyelinated axons are rendered susceptible to degeneration through loss of trophic support from oligodendrocytes and myelin, and this process underlies disability progression in multiple sclerosis. Promoting remyelination is a promising neuroprotective therapeutic strategy, but to date, has not been achieved through simply promoting oligodendrocyte precursor cell differentiation, and it is clear that a detailed understanding of the molecular mechanisms underlying failed remyelination is required to guide future therapeutic approaches. In multiple sclerosis, remyelination is impaired by extrinsic inhibitory cues in the lesion microenvironment including secreted effector molecules released from compartmentalized immune cells and reactive glia, as well as by intrinsic defects in oligodendrocyte lineage cells, most notably increased metabolic demands causing oxidative stress and accelerated cellular senescence. Promising advances in our understanding of the cellular and molecular mechanisms underlying these processes offers hope for strategically designed interventions to facilitate remyelination thereby resulting in robust clinical benefits.     

Targeting toll-like receptor 4 to modulate neuroinflammation in central nervous system disorders

ABSTRACT

Introduction: Adverse immune activation contributes to many central nervous system (CNS) disorders. All main CNS cell types express toll-like receptor 4 (TLR 4). This receptor is critical for a myriad of immune functions such as cytokine secretion and phagocytic activity of microglia; however, imbalances in TLR 4 activation can contribute to the progression of neurodegenerative diseases.

Areas covered: We considered available evidence implicating TLR 4 activation in the following CNS pathologies: Alzheimer’s disease, Parkinson’s disease, ischemic stroke, traumatic brain injury, multiple sclerosis, multiple systems atrophy, and Huntington’s disease. We reviewed studies reporting effects of TLR 4-specific antagonists and agonists in models of peripheral and CNS diseases from the perspective of possible future use of TLR 4 ligands in CNS disorders.

Expert opinion: TLR 4-specific antagonists could suppress neuroinflammation by reducing overproduction of inflammatory mediators; however, they may interfere with protein clearance mechanisms and myelination. Agonists that specifically activate myeloid differentiation primary-response protein 88 (MyD88)-independent pathway of TLR 4 signaling could facilitate beneficial glial phagocytic activity with limited activity as inducers of proinflammatory mediators. Deciphering the disease stage-specific involvement of TLR 4 in CNS pathologies is crucial for the future clinical development of TLR 4 agonists and antagonists.