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Re-WRAP (Remyelination for women at risk of axonal loss and progression): A phase II randomized placebo-controlled delayed-start trial of bazedoxifene for myelin repair in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a major cause of disability in young and middle-aged people, and myelin repair therapies are needed to slow or potentially reverse this damage. Bazedoxifene (BZA) is a selective estrogen receptor modulator identified in a novel high-throughput unbiased screen for its remyelinating potential, and its remyelinating effects were demonstrated in pre-clinical models. METHODS: This is a single-center, double blind, randomized, controlled, delayed-start Phase 2 clinical trial (NCT04002934) investigating the remyelinating effects of BZA relative to placebo. Fe

Multimodal imaging of subventricular zone neural stem/progenitor cells in the cuprizone mouse model reveals increased neurogenic potential for the olfactory bulb pathway, but no contribution to remyelination of the corpus callosum.

Multiple sclerosis is a devastating demyelinating disease of the central nervous system (CNS) in which endogenous remyelination, and thus recovery, often fails. Although the cuprizone mouse model allowed elucidation of many molecular factors governing remyelination, currently very little is known about the spatial origin of the oligodendrocyte progenitor cells that initiate remyelination in this model. Therefore, we here investigated in this model whether subventricular zone (SVZ) neural stem/progenitor cells (NSPCs) contribute to remyelination of the splenium following cuprizone-induced demye…

Воспаление микроглии коррелируется с поврежденным созреванием олигодендроцита при множественном склерозе.

ВВЕДЕНИЕ: Ремимилинизация демиелиновых аксонов может происходить как внутренний механизм ремонта при множественном склерозе (MS), однако его эффективность варьируется как от отдельных лиц, так и от повреждений MS. Молекулярные и клеточные механизмы, стимулирующие воспоминание, по-прежнему плохо понимаются. Здесь мы изучили связь между активацией микроглии и активностью ремиэлирования в MS.МЕТОДЫ: Мы соотносили регенеративную (CD163+) и воспалительную (iNOS+) микроглию с BCAS1+ олигодендроцитами, подразделяясь на ранние стадии (<3 процессы) и поздние (≥3 процессы) клетки в мозговых донорах с вы

Совпадение в аннотации оригинала
INTRODUCTION: Remyelination of demyelinated axons can occur as an endogenous repair mechanism in multiple sclerosis (MS), but its efficacy varies between both MS individuals and lesions. The molecular and cellular mechanisms that drive remyelination remain poorly understood. Here, we studied the relation between microglia activation and remyelination activit…

CEMIP Hyaluronidase растёт в Oligodendrocyte Progenitor Cells и Inhibits Oligodendrocyte Maturation.

Обезвоживание центральной нервной системы (ЦСН) происходит в многочисленных условиях, включая множественный склероз (МС). КНС предусматривает набор и созревание ячеек потомства олигодендроцитов (КОД). Ремилинизация часто не дает результатов отчасти из-за ингибирования ОРХ в миелионирующие олигодендроциты (ОИ). Продукты диагностирования гликосаминогликанского гиалуронана (HA), полученные в результате гиалуронидозной активности, создания блока OPS созревания и ремиелинирования. Здесь мы стремились определить, какие гиалурониды повышены в демиелионирующих повреждениях, и проверить, влияют ли они

Совпадение в аннотации оригинала
Central nervous system (CNS) demyelination occurs in numerous conditions including multiple sclerosis (MS). CNS remyelination involves recruitment and maturation of oligodendrocyte progenitor cells (OPCs). Remyelination often fails in part due to the inhibition of OPC maturation into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminogl…

Zebrafish regenerate full thickness optic nerve myelin after demyelination, but this fails with increasing age.

INTRODUCTION: In the human demyelinating central nervous system (CNS) disease multiple sclerosis, remyelination promotes recovery and limits neurodegeneration, but this is inefficient and always ultimately fails. Furthermore, these regenerated myelin sheaths are thinner and shorter than the original, leaving the underlying axons potentially vulnerable. In rodent models, CNS remyelination is more efficient, so that in young animals (but not old) the number of myelinated axons is efficiently restored to normal, but in both young and old rodents, regenerated myelin sheaths are still short and thi…

Myelin Repair as a Neuroprotective Strategy for Multiple Sclerosis: From Bench to Bedside.

Multiple sclerosis (MS) is a neuro-inflammatory disease characterized by demyelination in the central nervous system (CNS). Although a substantial endogenous capacity for remyelination has been demonstrated, this process is frequently incomplete and exhibits marked intra- and inter-individual heterogeneity. Several factors influence the extent of spontaneous myelin regeneration, including age, sex, disease course, and lesion localization. Oligodendrocytes (OL), derived from oligodendrocyte progenitor cells (OPCs), are the principal myelinating cells of the CNS. The regenerative cascade involve…

Brain region dependent molecular signatures and myelin repair following chronic demyelination.

Multiple sclerosis (MS) is the most prevalent demyelinating disease of the central nervous system, characterized by myelin destruction, axonal degeneration, and progressive loss of neurological functions. Remyelination is considered an axonal protection strategy and may enable functional recovery, but the mechanisms of myelin repair, especially after chronic demyelination, remain poorly understood. Here, we used the cuprizone demyelination mouse model to investigate spatiotemporal characteristics of acute and chronic de- and remyelination and motor functional recovery following chronic demyeli…

Oligodendrocyte precursor cells as a therapeutic target for demyelinating diseases.

The mechanisms regulating differentiation of multipotent oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs) are critical to our understanding of myelination and remyelination. Following acute demyelination in the central nervous system, adult OPCs migrate to the injury site, differentiate into OLs and generate new myelin sheaths. A common feature of regenerative processes is the fact that remyelination efficiency declines with aging and, accounts for the observation that chronic demyelinating diseases like multiple sclerosis (MS) are characterized by an ineffective remy…

Платежечки во время ремонта Myelin в Множестве склероза: друг или Фо?

Множественный склероз (MS) — аутоиммунный нейро-воспалительный демиелинирующий болезень центральной нервной системы (CNS), от которого страдает более 2,5 миллиона человек во всем мире. Ремиэлизация представляет собой мощную регенеративную реакцию на повреждение миэлина; однако на более поздних этапах НР этот процесс в значительной степени провалился. После обезвоживания олигодендроциты потомства (ОПС) распространяются, мигрируют и делятся на зрелые ремиелинирующие олигодендроциты. Почему воспоминание провалилось в склерозах? Платечки маленькие, овальные, ануклеативные клетки, которые циркулиру

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is an autoimmune neuroinflammatory demyelinating disease of the central nervous system (CNS) that affects more than 2.5 million people worldwide. Remyelination represents a robust regenerative response to myelin damage; however, during the later stages of MS, this process largely fails. Upon demyelination, oligodendrocyte progenitor c…

Spatiotemporal APLNR Expression Dynamics During Oligodendroglial Remodeling of the Corpus Callosum in the Cuprizone Model.

Demyelinating disorders such as multiple sclerosis are characterized by oligodendrocyte loss and insufficient remyelination. The cuprizone model provides a well-established experimental system for studying these processes. The apelinergic system, including the apelin receptor (APLNR), has been implicated in neuroprotection and central nervous system homeostasis. However, its role in white matter demyelination and repair remains incompletely understood. This study aimed to characterize the spatial and temporal dynamics of APLNR expression in relation to oligodendrocyte lineage cells in the corp…

Neuregulin-1 controls an endogenous repair mechanism after spinal cord injury.

Following traumatic spinal cord injury, acute demyelination of spinal axons is followed by a period of spontaneous remyelination. However, this endogenous repair response is suboptimal and may account for the persistently compromised function of surviving axons. Spontaneous remyelination is largely mediated by Schwann cells, where demyelinated central axons, particularly in the dorsal columns, become associated with peripheral myelin. The molecular control, functional role and origin of these central remyelinating Schwann cells is currently unknown. The growth factor neuregulin-1 (Nrg1, encode…

Erbin is required for myelination in regenerated axons after injury.

Neuregulin 1 (NRG1) is an axon-derived factor that is critical for Schwann cell (SC) development and myelinogenesis in a manner dependent on transmembrane tyrosine kinases ErbB2 and ErbB3. Recent studies suggest that NRG1 signaling plays a role in remyelination of regenerated nerves after injury. In this study, we investigated the role of Erbin, a protein that interacts with ErbB2 in remyelination of injured nerves. We show that Erbin expression increased dramatically in injured nerves. Myelinated axons were fewer, and g-ratios of those that were myelinated were increased in erbin(-/-) mice, w…

Pilot functional magnetic resonance imaging study of clemastine-aided functional recovery on a mouse model of demyelination.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease characterized by autoimmune attacks on myelin sheaths. Its deleterious effects may be reversed by remyelination, a process that restores the integrity of myelin sheaths and, consequently, neuronal function. However, the functional implications of demyelination and remyelination in MS, as well as the potential impact of therapeutic interventions, remain incompletely understood. We used noninvasive longitudinal resting-state functional magnetic resonance imaging in a cuprizone murine model of demyelination to investigate thes…

In vivo imaging reveals mature Oligodendrocyte division in adult Zebrafish.

Whether mature oligodendrocytes (mOLs) participate in remyelination has been disputed for several decades. Recently, some studies have shown that mOLs participate in remyelination by producing new sheaths. However, whether mOLs can produce new oligodendrocytes by asymmetric division has not been proven. Zebrafish is a perfect model to research remyelination compared to other species. In this study, optic nerve crushing did not induce local mOLs death. After optic nerve transplantation from olig2:eGFP fish to AB/WT fish, olig2+ cells from the donor settled and rewrapped axons in the recipient. …

Рецепты печени X: терапевтическая цель в демиелионирующих расстройствах.

Печень X Receptors (LXRα и LXRβ) — ядерные рецепторы, регулирующие различные метаболические процессы с помощью транскрипционного регулирования, включая гомеостазиз липидов и холестерина. Последние данные свидетельствуют об участии активации LXR в синтезе и техническом обслуживании миелина. Учитывая важнейшую роль миелина в нейрональной коммуникации, его потеря в таких расстройствах, как множественный склероз и болезнь Альцгеймера, подчеркивает настоятельную необходимость эффективной ремиелионирующей терапии. Восстановление функций олигодендроцитов для стимулирования ремиэлизации предлагает инт

Совпадение в аннотации оригинала
Liver X Receptors (LXRα and LXRβ) are nuclear receptors that regulate various metabolic processes via transcriptional regulation, including … eed for effective remyelinating therapies. Restoring the functions of oligodendrocytes to stimulate remyelination offers an interesting approach to protect neurons and slow down neurodegeneration. LXRs have been suggested as potential therapeutic targets in demyelinating disorders as they can promote cholesterol turnover and reduce inflammation, creating a favo …

Mechanisms of myelin repair, MRI techniques and therapeutic opportunities in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The remyelination process requires the activation, migration and differentiation of oligodendrocyte progenitor cells (OPC) in demyelinated areas. The metabolic dysfunction in chronic demyelinating lesions impairs the activation of OPCs, the myelin debris clearance by microglia decreases with age, along with diminished secretion of factors promoting OPC differentiation. Conventional magnetic resonance imaging (MRI) sequences have limited ability to differentiate unmyelinated and remyelin…

Matrix metalloprotease-9 modulates microglial/macrophage responses in murine brain demyelination.

Multiple sclerosis (MS) is a chronic autoimmune disorder, in which the immune system targets the protective myelin sheath surrounding axons in the brain, spinal cord and optic nerve, leading to demyelination and ultimately neurodegeneration. Promoting remyelination to delay or halt disease progression remains a major therapeutic challenge in MS research. Matrix metalloproteases (MMPs) have been implicated in the pathogenesis of MS. Elevated levels of MMP-9 have been detected in cerebrospinal fluid (CSF), serum and demyelinating lesions of MS patients, where MMP-9 contributes to myelin breakdow…

The development of myelin repair agents for treatment of multiple sclerosis: progress and challenges.

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder which affects the central nervous system. Multiple sclerosis treatment has traditionally focused on preventing inflammatory damage to the myelin sheath. Indeed, all currently available disease modifying agents are immunomodulators. However, the limitations of this approach are becoming increasingly clear, leading to the exploration of other potential therapeutic strategies. In particular, targeting the endogenous remyelination system to promote replacement of the lost myelin sheath has shown much promise. As our understanding of…

SIRT6 modulates lesion microenvironment in LPC induced demyelination by targeting astrocytic CHI3L1.

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced…

Нейротерапевтическое воздействие ванильной кислоты и ибудиласта на модель капризона множественного склероза.

Множественный склероз (MS) влияет 2.8 million люди по всему миру. Хотя причина неизвестна, могут возникнуть различные факторы риска. MS включает иммунную систему, атакующую миелиновую оболочку центральной нервной системы, что приводит к повреждениям нейронов. В этом исследовании для моделирования процесса обезвоживания/восстановления MS была использована мышь, опьяненная купризоной (CPZ). Она провела оценку молекулярного, гистологического и поведенческого воздействия ваниллиновой кислоты (ВА), естественной фенолической кислоты, в одиночку и с помощью ибудиласта (IBD), клинически испытанного ле

Совпадение в аннотации оригинала
Multiple sclerosis (MS) affects 2.8 million people worldwide. Although the cause is unknown, various risk factors might be involved. MS involves the immune system attacking the central nervous system's myelin sheath, leading to neuron damage. This study used a cuprizone (CPZ)-intoxicated mouse model to simulate MS's demyelination/remyelination process. It ev…