Sox2-mediated transdifferentiation of hAT-MSCs into induced neural progenitor-like cells for remyelination therapies.

Mesenchymal stem cells (MSCs) are converted to neural cells using growth factors and chemicals. Although these neural cells are effective at modulating disease symptoms, they are less effective at replacing lost neural cells. Direct transdifferentiation seems to be a promising method for generating the required cells for regenerative medicine applications. Sox2 is a key transcription factor in neural progenitor (NP) fate determination and has been frequently used for transdifferentiating different cell types to NPs. Here, we demonstrated that the overexpression of a single transcription factor, Sox2, in human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) led to the generation of induced NPs-like cells that were clonogenic, proliferative and passageable, and showed the potential to differentiate into three neural lineages. NPs are known as progenitors with the potential to differentiate into oligodendrocytes. In vivo, following transplantation into demyelinated adult mouse brains, they survived, differentiated and integrated into the adult brain while participating in the remyelination process and behavioral improvement. This report introduces a beneficial, low-cost and effective approach for generating NPs from an accessible adult source for autologous applications in treating neurodegenerative diseases, including remyelination therapies for multiple sclerosis and other demyelinating diseases.

Deferiprone promoted remyelination and functional recovery through enhancement of oligodendrogenesis in experimental demyelination animal model.

Remyelination refers to myelin regeneration, which reestablishes metabolic supports to axons. However, remyelination often fails in multiple sclerosis (MS), leading to chronic demyelination and axonal degeneration. Therefore, pharmacological approaches toward enhanced remyelination are highly demanded. Recently, deferiprone (DFP) was reported to exert neuroprotective effects, besides its iron-chelating ability. Since DFP exerts protective effects through various mechanisms, which share several factors with myelin formation process, we aimed to investigate the effects of DFP treatment on remyelination. Focal demyelination was induced by injection of lysolecithin, into the optic nerve of male C57BL/6J mice. The animals were treated with DFP/vehicle, starting from day 7 and continued during the myelin repair period. Histopathological, electrophysiological, and behavioral studies were used to evaluate the outcomes. Results showed that DFP treatment enhanced remyelination, decreased g-ratio and increased myelin thickness. At the mechanistic level, DFP enhanced oligodendrogenesis and ameliorated gliosis during the remyelination period. Furthermore, our results indicated that enhanced remyelination led to functional recovery as evaluated by the electrophysiological and behavioral tests. Even though the exact molecular mechanisms by which DFP-enhanced myelin repair remain to be elucidated, these results raise the possibility of using deferiprone as a therapeutic agent for remyelination therapy in MS.

Neutral or Detrimental Effects of TREM2 Agonist Antibodies in Preclinical Models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.

Long-term demyelination and aging-associated changes in mice corpus callosum; evidence for the role of accelerated aging in remyelination failure in a mouse model of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder affecting the central nervous system. Evidence suggests that age-related neurodegeneration contributes to disability progression during the chronic stages of MS. Aging is characterized by decreased regeneration potential and impaired myelin repair in the brain. It is hypothesized that accelerated cellular aging contributes to the functional decline associated with neurodegenerative diseases. We assessed the impact of aging on myelin content in the corpus callosum (CC) and compared aging with the long-term demyelination (LTD) consequents induced by 12 weeks of feeding with a cuprizone (CPZ) diet. Initially, evaluating myelin content in 2-, 6-, and 18-month-old mice revealed a reduction in myelin content, particularly at 18 months. Myelin thickness was decreased and the g-ratio increased in aged mice. Although a lower myelin content and higher g-ratio were observed in LTD model mice, compared to the normally aged mice, both aging and LTD exhibited relatively similar myelin ultrastructure. Our findings provide evidence that LTD exhibits the hallmarks of aging such as elevated expression of senescence-associated genes, mitochondrial dysfunction, and high level of oxidative stress as observed following normal aging. We also investigated the senescence-associated ß-galactosidase activity in O4+ late oligodendrocyte progenitor cells (OPCs). The senescent O4+/ß-galactosidase+ cells were elevated in the CPZ diet. Our data showed that the myelin degeneration in CC occurs throughout the lifespan, and LTD induced by CPZ accelerates the aging process which may explain the impairment of myelin repair in patients with progressive MS.

Conversion of Astrocyte Cell Lines to Oligodendrocyte Progenitor Cells Using Small Molecules and Transplantation to Animal Model of Multiple Sclerosis.

Astrocytes, the most prevalent cells in the central nervous system (CNS), can be transformed into neurons and oligodendrocyte progenitor cells (OPCs) using specific transcription factors and some chemicals. In this study, we present a cocktail of small molecules that target different signaling pathways to promote astrocyte conversion to OPCs. Astrocytes were transferred to an OPC medium and exposed for five days to a small molecule cocktail containing CHIR99021, Forskolin, Repsox, LDN, VPA and Thiazovivin before being preserved in the OPC medium for an additional 10 days. Once reaching the OPC morphology, induced cells underwent immunocytofluorescence evaluation for OPC markers while checked for lacking the astrocyte markers. To test the in vivo differentiation capabilities, induced OPCs were transplanted into demyelinated mice brains treated with cuprizone over 12 weeks. Two distinct lines of astrocytes demonstrated the potential of conversion to OPCs using this small molecule cocktail as verified by morphological changes and the expression of PDGFR and O4 markers as well as the terminal differentiation to oligodendrocytes expressing MBP. Following transplantation into demyelinated mice brains, induced OPCs effectively differentiated into mature oligodendrocytes. The generation of OPCs from astrocytes via a small molecule cocktail may provide a new avenue for producing required progenitors necessary for myelin repair in diseases characterized by the loss of myelin such as multiple sclerosis.

Myelin repair of spinal cord injury in adult mice induced by treadmill training upregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha.

Growing evidence has proven the efficacy of physical exercise in remyelination and motor function performance after spinal cord injury (SCI). However, the molecular mechanisms of treadmill training on myelin repair and functional recovery after SCI have not yet been fully studied. Here, we explored the effect of treadmill training on upregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α)-mediated myelin repair and functional recovery in a mouse model of thoracic T10 contusion injury. A 4-week treadmill training scheme was conducted on mice with SCI. The expression levels of oligodendrogenesis-related protein and PGC1α were detected by immunofluorescence, RNA fluorescence in situ hybridization and western blotting. Transmission electron microscopy (TEM) was used to observe myelin structure. The Basso Mouse Scale (BMS) and CatWalk automated gait analysis system were used for motor function recovery evaluation. Motor evoked potentials (MEPs) were also identified. In addition, adeno-associated virus (AAV)-mediated PGC1α knockdown in OLs was used to further unravel the role of PGC1α in exercise-induced remyelination. We found that treadmill training boosts oligodendrocyte precursor cells (OPCs) proliferation, potentiates oligodendrocytes (OLs) maturation, and increases myelin-related protein and myelin sheath thickness, thus impelling myelin repair and hindlimb functional performance as well as the speed and amplitude of nerve conduction after SCI. Additionally, downregulating PGC1α through AAV attenuated these positive effects of treadmill training. Collectively, our results suggest that treadmill training enhances remyelination and functional recovery by upregulating PGC1α, which should provide a step forward in the understanding of the effects of physical exercise on myelin repair.

The role and mechanism of purinergic signaling in oligodendrocytes development and myelin repair:A literature review / 实用医学杂志

Oligodendrocytes(OLs)play a crucial role in myelination during the development and repair of the central nervous system.ATP serves not only as an important signaling molecule involving in the intercellular com-munications,but also as an energetic molecule,with its purinergic receptor subtypes widely present in neurons and glial cells.These subtypes are composed of two purinergic receptors:P1 and P2:The former are primarily activated by adenosine,and the latter mainly by ATP,ADP,and UTP.The two receptors paly their respective role in various regions of the CNS under physiological or pathological conditions through distinct mechanisms.In this paper,we review recent literature on the roles and mechanisms of the purinergic receptors in OL development,myelination,and myelin repair.It may be of great significance for further understanding the role of purinergic signaling in demy-elinating diseases and myelin dysplasia and exploring potential therapeutic targets.

Sanguinarine modulates microglial function via PPARγ activation and protects against CNS demyelination.

Microglia aggregate in regions of active inflammation and demyelination in the CNS of multiple sclerosis (MS) patients and are considered pivotal in the disease process. Targeting microglia is a promising therapeutic approach for myelin repair. Previously, we identified two candidates for microglial modulation and remyelination using a Connectivity Map (CMAP)-based screening strategy. Interestingly, with results that overlapped, sanguinarine (SAN) emerged as a potential drug candidate to modulate microglial polarization and promote remyelination. In the current study, we demonstrate the efficacy of SAN in mitigating the MS-like experimental autoimmune encephalomyelitis (EAE) in a dose-dependent manner. Meanwhile, prophylactic administration of a medium dose (2.5 mg/kg) significantly reduces disease incidence and ameliorates clinical signs in EAE mice. At the cellular level, SAN reduces the accumulation of microglia in the spinal cord. Morphological analyses and immunophenotyping reveal a less activated state of microglia following SAN administration, supported by decreased inflammatory cytokine production in the spinal cord. Mechanistically, SAN skews primary microglia towards an immunoregulatory state and mitigates proinflammatory response through PPARγ activation. This creates a favorable milieu for the differentiation of oligodendrocyte progenitor cells (OPCs) when OPCs are incubated with conditioned medium from SAN-treated microglia. We further extend our investigation into the cuprizone-induced demyelinating model, confirming that SAN treatment upregulates oligodendrocyte lineage genes and increases myelin content, further suggesting its pro-myelination effect. In conclusion, our data propose SAN as a promising candidate adding to the preclinical therapeutic arsenal for regulating microglial function and promoting myelin repair in CNS demyelinating diseases such as MS.

The AMPK activator metformin improves recovery from demyelination by shifting oligodendrocyte bioenergetics and accelerating OPC differentiation.

Multiple Sclerosis (MS) is a chronic disease characterized by immune-mediated destruction of myelinating oligodendroglia in the central nervous system. Loss of myelin leads to neurological dysfunction and, if myelin repair fails, neurodegeneration of the denuded axons. Virtually all treatments for MS act by suppressing immune function, but do not alter myelin repair outcomes or long-term disability. Excitingly, the diabetes drug metformin, a potent activator of the cellular "energy sensor" AMPK complex, has recently been reported to enhance recovery from demyelination. In aged mice, metformin can restore responsiveness of oligodendrocyte progenitor cells (OPCs) to pro-differentiation cues, enhancing their ability to differentiate and thus repair myelin. However, metformin's influence on young oligodendroglia remains poorly understood. Here we investigated metformin's effect on the temporal dynamics of differentiation and metabolism in young, healthy oligodendroglia and in oligodendroglia following myelin damage in young adult mice. Our findings reveal that metformin accelerates early stages of myelin repair following cuprizone-induced myelin damage. Metformin treatment of both isolated OPCs and oligodendrocytes altered cellular bioenergetics, but in distinct ways, suppressing oxidative phosphorylation and enhancing glycolysis in OPCs, but enhancing oxidative phosphorylation and glycolysis in both immature and mature oligodendrocytes. In addition, metformin accelerated the differentiation of OPCs to oligodendrocytes in an AMPK-dependent manner that was also dependent on metformin's ability to modulate cell metabolism. In summary, metformin dramatically alters metabolism and accelerates oligodendroglial differentiation both in health and following myelin damage. This finding broadens our knowledge of metformin's potential to promote myelin repair in MS and in other diseases with myelin loss or altered myelination dynamics.

Transgenic expression of the HERV-W envelope protein leads to polarized glial cell populations and a neurodegenerative environment.

The human endogenous retrovirus type W (HERV-W) has been identified and repeatedly confirmed as human-specific pathogenic entity affecting many cell types in multiple sclerosis (MS). Our recent contributions revealed the encoded envelope (ENV) protein to disturb myelin repair by interfering with oligodendroglial precursor differentiation and by polarizing microglial cells toward an axon-damage phenotype. Indirect proof of ENV's antiregenerative and degenerative activities has been gathered recently in clinical trials using a neutralizing anti-ENV therapeutic antibody. Yet direct proof of its mode of action can only be presented here based on transgenic ENV expression in mice. Upon demyelination, we observed myelin repair deficits, neurotoxic microglia and astroglia, and increased axon degeneration. Experimental autoimmune encephalomyelitis activity progressed faster in mutant mice equally accompanied by activated glial cells. This study therefore provides direct evidence on HERV-W ENV's contribution to the overall negative impact of this activated viral entity in MS.

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. Female patients with relapsing-remitting MS, aged 45-60 years (or > 40 if post-menopausal), and ambulatory status (EDSS 0-6 inclusive), will be recruited into a clinical trial with 2 arms of identical design, except that the "Chronic Optic Neuropathy" arm requires additional inclusion criteria of electrophysiological evidence of prior visual pathway demyelination. Clinical, electrophysiological, and imaging evaluations will occur at baseline, 3 months, and 6 months. The primary outcome is change in Myelin Water Fraction (MWF) on MRI within the corpus callosum. Secondary outcomes are: visual evoked potential (VEP) P100 latency, novel digital measures of cognition and activity, and patient reported outcomes. Tertiary outcomes are: safety and tolerability. DISCUSSION: BZA has strong preclinical effects on myelin repair, and in the general population demonstrated benefits in treating postmenopausal osteoporosis. Together, these findings support the rationale for an RCT testing BZA in women with MS, evaluating established neuroimaging and neurovisual measures of myelin repair. Additionally, validating novel digital tools could increase sensitivity to change and inform the duration and design of future clinical trials.

A Novel Ex Vivo Model to Study Therapeutic Treatments for Myelin Repair following Ischemic Damage.

Stroke is a major reason for persistent disability due to insufficient treatment strategies beyond reperfusion, leading to oligodendrocyte death and axon demyelination, persistent inflammation and astrogliosis in peri-infarct areas. After injury, oligodendroglial precursor cells (OPCs) have been shown to compensate for myelin loss and prevent axonal loss through the replacement of lost oligodendrocytes, an inefficient process leaving axons chronically demyelinated. Phenotypic screening approaches in demyelinating paradigms revealed substances that promote myelin repair. We established an ex vivo adult organotypic coronal slice culture (OCSC) system to study repair after stroke in a resource-efficient way. Post-photothrombotic OCSCs can be manipulated for 8 d by exposure to pharmacologically active substances testing remyelination activity. OCSCs were isolated from a NG2-CreERT2-td-Tomato knock-in transgenic mouse line to analyze oligodendroglial fate/differentiation and kinetics. Parbendazole boosted differentiation of NG2+ cells and stabilized oligodendroglial fate reflected by altered expression of associated markers PDGFR-α, CC1, BCAS1 and Sox10 and GFAP. In vitro scratch assay and chemical ischemia confirmed the observed effects upon parbendazole treatment. Adult OCSCs represent a fast, reproducible, and quantifiable model to study OPC differentiation competence after stroke. Pharmacological stimulation by means of parbendazole promoted OPC differentiation.

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 demyelination. Extensive remyelination occurred after both the acute and chronic insults, but with less robust glial responses and slower myelin recovery in the chronic phase. Axonal damage was found at the ultrastructural level in the chronically demyelinated corpus callosum and in remyelinated axons in the somatosensory cortex. Unexpectedly, we observed the development of functional motor deficits after chronic remyelination. RNA sequencing of isolated brain regions revealed significantly altered transcripts across the corpus callosum, cortex and hippocampus. Pathway analysis identified selective upregulation of extracellular matrix/collagen pathways and synaptic signaling in the chronically de/remyelinating white matter. Our study demonstrates regional differences of intrinsic reparative mechanisms after a chronic demyelinating insult and suggests a potential link between long-term motor function alterations and continued axonal damage during chronic remyelination. Moreover, the transcriptome dataset of three brain regions and over an extended de/remyelination period provides a valuable platform for a better understanding of the mechanisms of myelin repair as well as the identification of potential targets for effective remyelination and neuroprotection for progressive MS.

Chronic demyelination and myelin repair after spinal cord injury in mice: A potential link for glutamatergic axon activity.

Our prior work examining endogenous repair after spinal cord injury (SCI) in mice revealed that large numbers of new oligodendrocytes (OLs) are generated in the injured spinal cord, with peak oligodendrogenesis between 4 and 7 weeks post-injury (wpi). We also detected new myelin formation over 2 months post-injury (mpi). Our current work significantly extends these results, including quantification of new myelin through 6 mpi and concomitant examination of indices of demyelination. We also examined electrophysiological changes during peak oligogenesis and a potential mechanism driving OL progenitor cell (OPC) contact with axons. Results reveal peak in remyelination occurs during the 3rd mpi, and that myelin generation continues for at least 6 mpi. Further, motor evoked potentials significantly increased during peak remyelination, suggesting enhanced axon potential conduction. Interestingly, two indices of demyelination, nodal protein spreading and Nav1.2 upregulation, were also present chronically after SCI. Nav1.2 was expressed through 10 wpi and nodal protein disorganization was detectable throughout 6 mpi suggesting chronic demyelination, which was confirmed with EM. Thus, demyelination may continue chronically, which could trigger the long-term remyelination response. To examine a potential mechanism that may initiate post-injury myelination, we show that OPC processes contact glutamatergic axons in the injured spinal cord in an activity-dependent manner. Notably, these OPC/axon contacts were increased 2-fold when axons were activated chemogenetically, revealing a potential therapeutic target to enhance post-SCI myelin repair. Collectively, results show the surprisingly dynamic nature of the injured spinal cord over time and that the tissue may be amenable to treatments targeting chronic demyelination.

Enhancing axonal myelination in seniors: A review exploring the potential impact cannabis has on myelination in the aged brain.

Consumption of cannabis is on the rise as public opinion trends toward acceptance and its consequent legalization. Specifically, the senior population is one of the demographics increasing their use of cannabis the fastest, but research aimed at understanding cannabis' impact on the aged brain is still scarce. Aging is characterized by many brain changes that slowly alter cognitive ability. One process that is greatly impacted during aging is axonal myelination. The slow degradation and loss of myelin (i.e., demyelination) in the brain with age has been shown to associate with cognitive decline and, furthermore, is a common characteristic of numerous neurological diseases experienced in aging. It is currently not known what causes this age-dependent degradation, but it is likely due to numerous confounding factors (i.e., heightened inflammation, reduced blood flow, cellular senescence) that impact the many cells responsible for maintaining overall homeostasis and myelin integrity. Importantly, animal studies using non-human primates and rodents have also revealed demyelination with age, providing a reliable model for researchers to try and understand the cellular mechanisms at play. In rodents, cannabis was recently shown to modulate the myelination process. Furthermore, studies looking at the direct modulatory impact cannabis has on microglia, astrocytes and oligodendrocyte lineage cells hint at potential mechanisms to prevent some of the more damaging activities performed by these cells that contribute to demyelination in aging. However, research focusing on how cannabis impacts myelination in the aged brain is lacking. Therefore, this review will explore the evidence thus far accumulated to show how cannabis impacts myelination and will extrapolate what this knowledge may mean for the aged brain.

Cell-based experimental strategies for myelin repair in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS), diagnosed at a mean age of 32 years. CNS glia are crucial players in the onset of MS, primarily involving astrocytes and microglia that can cause/allow massive oligodendroglial cells death, without immune cell infiltration. Current therapeutic approaches are aimed at modulating inflammatory reactions during relapsing episodes, but lack the ability to induce very significant repair mechanisms. In this review article, different experimental approaches based mainly on the application of different cell types as therapeutic strategies applied for the induction of myelin repair and/or the amelioration of the disease are discussed. Regarding this issue, different cell sources were applied in various experimental models of MS, with different results, both in significant improvements in remyelination and the reduction of neuroinflammation and glial activation, or in neuroprotection. All cell types tested have advantages and disadvantages, which makes it difficult to choose a better option for therapeutic application in MS. New strategies combining cell-based treatment with other applications would result in further improvements and would be good candidates for MS cell therapy and myelin repair.

Myelin repair in Alzheimer's disease: a review of biological pathways and potential therapeutics.

This literature review investigates the significant overlap between myelin-repair signaling pathways and pathways known to contribute to hallmark pathologies of Alzheimer's disease (AD). We discuss previously investigated therapeutic targets of amyloid, tau, and ApoE, as well as other potential therapeutic targets that have been empirically shown to contribute to both remyelination and progression of AD. Current evidence shows that there are multiple AD-relevant pathways which overlap significantly with remyelination and myelin repair through the encouragement of oligodendrocyte proliferation, maturation, and myelin production. There is a present need for a single, cohesive model of myelin homeostasis in AD. While determining a causative pathway is beyond the scope of this review, it may be possible to investigate the pathological overlap of myelin repair and AD through therapeutic approaches.

CAQK, a peptide associating with extracellular matrix components targets sites of demyelinating injuries.

The destruction of the myelin sheath that encircles axons leads to impairments of nerve conduction and neuronal dysfunctions. A major demyelinating disorder is multiple sclerosis (MS), a progressively disabling disease in which immune cells attack the myelin. To date, there are no therapies to target selectively myelin lesions, repair the myelin or stop MS progression. Small peptides recognizing epitopes selectively exposed at sites of injury show promise for targeting therapeutics in various pathologies. Here we show the selective homing of the four amino acid peptide, cysteine-alanine-lysine glutamine (CAQK), to sites of demyelinating injuries in three different mouse models. Homing was assessed by administering fluorescein amine (FAM)-labeled peptides into the bloodstream of mice and analyzing sites of demyelination in comparison with healthy brain or spinal cord tissue. FAM-CAQK selectively targeted demyelinating areas in all three models and was absent from healthy tissue. At lesion sites, the peptide was primarily associated with the fibrous extracellular matrix (ECM) deposited in interstitial spaces proximal to reactive astrocytes. Association of FAM-CAQK was detected with tenascin-C although tenascin depositions made up only a minor portion of the examined lesion sites. In mice on a 6-week cuprizone diet, FAM-CAQK peptide crossed the nearly intact blood-brain barrier and homed to demyelinating fiber tracts. These results demonstrate the selective targeting of CAQK to demyelinating injuries under multiple conditions and confirm the previously reported association with the ECM. This work sets the stage for further developing CAQK peptide targeting for diagnostic and therapeutic applications aimed at localized myelin repair.

Ursolic Acid Enhances Myelin Repair in Adult Mice Brains and Stimulates Exhausted Oligodendrocyte Progenitors to Remyelinate.

In multiple sclerosis patients, long-term inflammation makes the oligodendrocyte progenitor cells (OPCs) exhausted; therefore, a new therapy that makes them responsive to insults to participate in remyelination is highly in demand. Here, we investigated the effect of ursolic acid (UA) on myelin repair after mid-term and long-term demyelination periods induced by 6 or 12 weeks of cuprizone treatment followed by 2 weeks of recovery with or without UA. Immunohistochemistry studies and myelin genes expression assessment were used to evaluate the myelination status of mouse corpora callosa and the cellular mechanisms of myelin repair. Results showed that UA significantly promoted recovery from myelin loss after discontinuing 6 or 12 weeks of cuprizone feeding, as measured by luxol fast blue (LFB), fluoroMyelin (FM), anti-myelin basic protein (MBP) staining, and oligodendrocyte progenitor cell counts. It led to reduced inflammation and gliosis as evaluated by glial fibrillary acidic protein (GFAP), Iba1, or other marker gene transcripts. Following long-term demyelination, gliosis and TNF-α were observed as potential players in lesion pathology, which were restored by UA. An increased IL-10 may contribute to UA anti-inflammatory effect and making responsive the exhausted OPCs. UA increased the number of new oligodendrocyte lineage cells and myelination. Our findings indicated that UA can enhance myelin repair after cuprizone challenge through the prevention of gliosis and increasing the newly generated myelin.

Matrine inhibits the Wnt3a/ß-catenin/TCF7L2 signaling pathway in experimental autoimmune encephalomyelitis.

Oligodendrocyte (OL) death and remyelination failure lead to progressive neurological deficits in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophora flavescens, has the capacity to effectively inhibit central nervous system (CNS) inflammation and to promote neuroregeneration. In the present study we explored its regulatory mechanism on the Wnt/ß-catenin/TCF7L2 pathway, a negative modulator for myelination, in MOG35--55 peptide-induced EAE. Our results clearly indicate that MAT treatment reduced the activation of Wnt3a and ß-catenin in the CNS of EAE mice, accompanied by the activation of GSK3ß and decreased expression of cyclin D1 and Axin2, two target genes of the Wnt3a/ß-catenin pathway. In addition, MAT increased OL maturation and myelination, as evidenced by the decreased number of NG2+Olig2+ cells and the increased numbers of MBP+ and CC1+Olig2+ cells. Taken together, these findings indicate that MAT treatment promoted the maturation of OLs and myelin repair, which is closely related to the modulation of the Wnt/ß-catenin/TCF7L2 signaling pathway.