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Targeting TrkB with a Brain-Derived Neurotrophic Factor Mimetic Promotes Myelin Repair in the Brain.

Methods to promote myelin regeneration in response to central myelin loss are essential to prevent the progression of clinical disability in demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to promote myelination during development via oligodendrocyte expressed TrkB receptors. Here, we use a structural mimetic of BDNF to promote myelin regeneration in a preclinical mouse model of central demyelination. In female mice, we show that selective targeting of TrkB with the BDNF-mimetic enhances remyelination, increasing oligodendrocyte differentiation, the f…

Targeting Smoothened as a New Frontier in the Functional Recovery of Central Nervous System Demyelinating Pathologies.

Myelin sheaths on vertebrate axons provide protection, vital support and increase the speed of neuronal signals. Myelin degeneration can be caused by viral, autoimmune or genetic diseases. Remyelination is a natural process that restores the myelin sheath and, consequently, neuronal function after a demyelination event, preventing neurodegeneration and thereby neuron functional loss. Pharmacological approaches to remyelination represent a promising new frontier in the therapy of human demyelination pathologies and might provide novel tools to improve adaptive myelination in aged individuals. R…

Histamine H2 receptor negatively regulates oligodendrocyte differentiation in neonatal hypoxic-ischemic white matter injury.

Neonatal hypoxic-ischemic encephalopathy (HIE) with the pathological characteristic of white matter injury often leads to lifelong cognitive and neurobehavioral dysfunction, but relevant therapies to promote remyelination are still unavailable. We found that histamine H2 receptor (H2R) negatively regulated the oligodendrocyte differentiation rate without affecting the oligodendrocytes at the oligodendrocyte precursor cell stage or mature stage following oxygen-glucose deprivation in vitro. Notably, selective deletion of the H2R gene (Hrh2) in differentiating oligodendrocytes (Hrh2fl/fl;CNPase-…

Spinal cord microglia exhibit a dysfunctional response to myelin damage.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that affects both the brain and spinal cord, although the brain has historically received greater attention. In the inducible, oligodendrocyte-specific knockout model of Myrf, which results in white matter damage to both the brain and spinal cord, our laboratory previously demonstrated that the brain undergoes remyelination following white matter damage, whereas the spinal cord has limited remyelination. We also observed that brain microglia display a much stronger activation than spinal cord microglia. Micr…

Effects of murine and human bone marrow-derived mesenchymal stem cells on cuprizone induced demyelination.

For the treatment of patients with multiple sclerosis there are no regenerative approaches to enhance remyelination. Mesenchymal stem cells (MSC) have been proposed to exert such regenerative functions. Intravenous administration of human MSC reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model mimicking some aspects of multiple sclerosis. However, it is not clear if this effect was achieved by systemic immunomodulation or if there is an active neuroregeneration in the central nervous system (CNS). In order to investigate remyelination and regenerat…

Selective GPR17 antagonism enhances structural and functional recovery in animal models of demyelination.

Myelination, driven by differentiation of oligodendrocyte precursor cells, is critical for metabolic and structural support and efficient ax … endrocyte precursor cell differentiation. To test the impact of pharmacological GPR17 inhibition on remyelination, we evaluated the effects of a novel, selective GPR17 antagonist in cuprizone-induced murine demyelination models. This toxin-induced approach has been widely used to study mechanisms of de- and remyelination, in the absence of the full inflammatory …

Reassembly of Excitable Domains after CNS Axon Regeneration.

UNLABELLED: Action potential initiation and propagation in myelinated axons require ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Disruption of these domains after injury impairs nervous system function. Traditionally, injured CNS axons are considered refractory to regeneration, but some recent approaches challenge this view by showing robust long-distance regeneration. However, whether these approaches allow remyelination and promote the reestablishment of AIS and nodes of Ranvier is unknown. Using mouse optic nerve crush as a model for CNS traumatic injury, we p…

CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model.

Demyelination in the central nervous system (CNS) is known to involve several immune effector mechanisms, including complement proteins. Local production of complement by glial cells in the brain can be both harmful and protective. To investigate the roles of C3a and C5a in demyelination and remyelination pathology we utilized the cuprizone model. Transgenic mice expressing C3a or C5a under the control of the glial fibrillary acidic protein (GFAP) promoter had exacerbated demyelination and slightly delayed remyelination in the corpus callosum compared to WT mice. C3a and C5a transgenic mice ha…

Oligodendrocyte progenitor cell-specific delivery of lipid nanoparticles loaded with Olig2 synthetically modified messenger RNA for ischemic stroke therapy.

The transcription factor Olig2 is highly expressed throughout oligodendroglial development and is needed for the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and remyelination. Although Olig2 overexpression in OPCs is a possible therapeutic target for enhancing myelin repair in ischemic stroke, achieving Olig2 overexpression in vivo remains a formidable technological challenge. To address this challenge, we employed lipid nanoparticle (LNP)-mediated delivery of Olig2 synthetically modified messenger RNA (mRNA) as a viable method for in vivo Olih2 protein ove…

Gender differences in the histopathology of MS?

Multiple sclerosis (MS) lesions are histopathologically characterized by inflammation, demyelination/remyelination, axonal damage and gliosis. Animal experimental and in vitro studies suggest that sex hormones influence the immune system and contribute to the increased likelihood in women of developing MS. However, a variety of studies have also shown that remyelination is more marked in female rodents or that female sex hormones are beneficial for myelin repair. To determine whether gender influences the histopathology of MS lesions, we compared the extent of inflammation, axonal damage and r…

Proteomics dataset of lysolecithin-induced demyelinated lesions in corpus callosum of Lewis rats, treated with Vagus nerve stimulation or sham treatment.

This article presents a comprehensive proteomics dataset from a lysolecithin (LPC)-induced demyelination model in the corpus callosum of female Lewis rats. The LPC model, widely used in preclinical studies of toxic demyelination, serves as a valuable tool for investigating processes of demyelination and remyelination, as well as for testing potential remyelination therapies for diseases like Multiple Sclerosis. In this study, rats received either Vagus Nerve Stimulation (VNS) or a sham treatment. Proteomic analysis via LC-MS/MS was performed to assess the impact of these treatments on inflamma…

Роль коллагена типа I в травме белой материи.

Увечье белой материи - патология мозга, отмеченная потерей олигодендроцитов и результирующим демиэлированием. Различные механизмы вызывают травму белой материи, включая ишемический инсульт и множественный склероз. Олигодендроциты регенерируют белую материю в центральной нервной системе в процессе, называемом ремиелинацией, волшебным демиелином аксонов с новым миелином. Несмотря на то, что сбой в ремии можно наблюдать при постепенном множественном склерозе и после ишемического инсульта, механизмы регенерации поврежденной белой материи остаются неясными. В этом обзоре мы в первую очередь концент

Совпадение в аннотации оригинала
White matter injury is a cerebral pathology marked by the loss of oligodendrocytes and the resultant demyelination. Various mechanisms induce white matter injury, including ischemic stroke and multiple sclerosis. Oligodendrocytes regenerate white matter in the central nervous system in a process called remyelination, ensheathing demyelinated axons with new m…

Multiple sclerosis. Pathology of recurrent lesions.

Recent autopsy studies suggest that remyelinated shadow plaques located in otherwise intact white matter are the outcome of a previous singl … ecurrent demyelination of the same area of white matter may be one of the factors underlying failed remyelination in multiple sclerosis.

Cryogel scaffolds for regionally constrained delivery of lysophosphatidylcholine to central nervous system slice cultures: A model of focal demyelination for multiple sclerosis research.

The pathology of multiple sclerosis (MS) is typified by focal demyelinated areas of the brain and spinal cord, which results in axonal degeneration and atrophy. Although the field has made much progress in developing immunomodulatory therapies to reduce the occurrence of these focal lesions, there is a conspicuous lack of licensed effective therapies to reduce axonal degeneration or promote repair. Remyelination, carried out by oligodendrocytes, does occur in MS, and is protective against axonal degeneration. Unfortunately, remyelination is not very efficient, and ultimately fails and so there…

Cuprizone demyelination of the corpus callosum in mice correlates with altered social interaction and impaired bilateral sensorimotor coordination.

For studies of remyelination in demyelinating diseases, the cuprizone model of CC (corpus callosum) demyelination has experimental advantages that include overall size, proximity to neural stem cells of the subventricular zone, and correlation with a lesion predilection site in multiple sclerosis. In addition, cuprizone treatment can be ended to allow more direct analysis of remyelination than with viral or autoimmune models. However, CC demyelination lacks a useful functional correlate in rodents for longitudinal analysis throughout the course of demyelination and remyelination. In the presen…

The Role of Sex Hormones in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelination disorder with an immune-mediated pathophysiology that affects the central nervous system (CNS). Like other autoimmune conditions, it has a predilection for female gender. This suggests a gender bias and a possible hormonal association. Inflammation and demyelination are hallmarks of MS. Oligodendrocytes are the myelinating cells of the CNS and these continue to be generated by oligodendrocyte precursor cells (OPCs). The process of remyelination represents a major form of plasticity in the developing adult CNS. Remyelination does o…

HB-EGF and EGF infusion following CNS demyelination mitigates age-related decline in regeneration of oligodendrocytes from neural precursor cells originating in the ventricular-subventricular zone.

In multiple sclerosis (MS), chronic demyelination initiated by immune-mediated destruction of myelin, leads to axonal damage and neuronal cell death, resulting in a progressive decline in neurological function. The development of interventions that potentiate remyelination could hold promise as a novel treatment strategy for MS. To this end, our group has demonstrated that neural precursor cells (NPCs) residing in the ventricular-subventricular zone (V-SVZ) of the adult mouse brain contribute significantly to remyelination in response to central nervous system (CNS) demyelination and can regen…

Дифференциальное воздействие протеина IL4I1 на лимфоциты от здоровых и многоклерозовых пациентов.

Множественный склероз (MS) — хроническое воспалительное заболевание, характеризующееся иммунопосредованным обезвоживанием центральной нервной системы, что приводит к значительному неврологическому дефициту и нарушению функции ремиелинирования. Мы уже обнаружили, что интерлейкин...four спровоцированные one (IL4I1) протеин модифицирует CNS воспаление и усиливает воспоминание в мышах моделей экспериментального обезвоживания. Однако остается неясным, регулирует ли IL4I1 лимфоцитную активность в MS. Чтобы оценить терапевтический потенциал IL4I1 в MS, мы изучили воздействие лечения IL4I1 на лимфоцит

Совпадение в аннотации оригинала
Multiple sclerosis (MS) is a chronic inflammatory disease characterized by immune-mediated demyelination of the central nervous system, resulting in extensive neurological deficit and remyelination impairment. We have previously found that interleukin-four induced one (IL4I1) protein modulates CNS inflammation and enhances remyelination in mouse models of ex…

Valproic Acid attenuates disease symptoms and increases endogenous myelin repair by recruiting neural stem cells and oligodendrocyte progenitors in experimental autoimmune encephalomyelitis.

BACKGROUND: inefficient remyelination of demyelinated plaques in multiple sclerosis (ms) leads to secondary axon degeneration and progressive disability. therapies that potentiate remyelination would be of immense help for managing MS. OBJECTIVE: Here, we report the effects of valproic acid (VPA) on focal experimental autoimmune encephalomyelitis (fEAE). METHODS: fEAE was induced in Wistar rats by immunizing the animals with guinea pig spinal cord homogenate emulsified in complete Freund's adjuvant and with pertussis toxin (PT) injection into the spinal cord at the level of T8 vertebra on da…

Transcranial alternating current stimulation at 10 Hz promotes oligodendrogenesis and reduces g-ratio after cuprizone-induced demyelination.

Multiple sclerosis (MS) is characterized by demyelination and incomplete remyelination. While numerous disease modifying treatments are available, none of these have been shown to aid in remyelination. In this study, we examined the remyelinating potential of transcranial alternating current stimulation (tACS) at 10 Hz in the cuprizone (CPZ) model. Our experiments show that 1 week of tACS during the recovery phase of the CPZ model could accelerate the maturation of newly formed oligodendrocytes and increase the relative myelin thickness of axons without changing the gross myelin content. Cogni…