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Chronic demyelination and oligodendrocyte loss deprive neurons of crucial support. It is the degeneration of neurons and their connections that drives progressive disability in demyelinating disease. However, whether chronic demyelination triggers neurodegeneration and how it may do so remain unclear. We characterize two genetic mouse models of inducible demyelination, one distinguished by effective remyelination and the other by remyelination failure and chronic demyelination. While both demyelinating lines feature axonal damage, mice with blocked remyelination have elevated neuronal apoptosis and altered microglial inflammation, whereas mice with efficient remyelination do not feature neuronal apoptosis and have improved functional recovery. Remyelination incapable mice show increased activation of kinases downstream of dual leucine zipper kinase (DLK) and phosphorylation of c-Jun in neuronal nuclei. Pharmacological inhibition or genetic disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. Together, we demonstrate that remyelination is associated with neuroprotection and identify DLK inhibition as protective strategy for chronically demyelinated neurons.

Multiple sclerosis (MS) is a chronic and debilitating neurological disease that results in inflammatory demyelination. While endogenous remyelination helps to recover function, this restorative process tends to become less efficient over time. Currently, intense efforts aimed at the mechanisms that promote remyelination are being considered promising therapeutic approaches. The M1 muscarinic acetylcholine receptor (M1R) was previously identified as a negative regulator of oligodendrocyte differentiation and myelination. Here, we validate M1R as a target for remyelination by characterizing expression in human and rodent oligodendroglial cells (including those in human MS tissue) using a highly selective M1R probe. As a breakthrough to conventional methodology, we conjugated a fluorophore to a highly M1R selective peptide (MT7) which targets the M1R in the subnanomolar range. This allows for exceptional detection of M1R protein expression in the human CNS. More importantly, we introduce PIPE-307, a brain-penetrant, small-molecule antagonist with favorable drug-like properties that selectively targets M1R. We evaluate PIPE-307 in a series of in vitro and in vivo studies to characterize potency and selectivity for M1R over M2-5R and confirm the sufficiency of blocking this receptor to promote differentiation and remyelination. Further, PIPE-307 displays significant efficacy in the mouse experimental autoimmune encephalomyelitis model of MS as evaluated by quantifying disability, histology, electron microscopy, and visual evoked potentials. Together, these findings support targeting M1R for remyelination and support further development of PIPE-307 for clinical studies.

BackgroundCystatin F is a secreted lysosomal cysteine protease inhibitor that has been implicated in affecting the severity of demyelination and enhancing remyelination in pre-clinical models of immune-mediated demyelination. How cystatin F impacts neurologic disease severity following viral infection of the central nervous system (CNS) has not been well characterized and was the focus of this study. We used cystatin F null-mutant mice (Cst7-/-) with a well-established model of murine coronavirus-induced neurologic disease to evaluate the contributions of cystatin F in host defense, demyelination and remyelination.MethodsWildtype controls and Cst7-/- mice were intracranially (i.c.) infected with a sublethal dose of the neurotropic JHM strain of mouse hepatitis virus (JHMV), with disease progression and survival monitored daily. Viral plaque assays and qPCR were used to assess viral levels in CNS. Immune cell infiltration into the CNS and immune cell activation were determined by flow cytometry and 10X genomics chromium 3' single cell RNA sequencing (scRNA-seq). Spinal cord demyelination was determined by luxol fast blue (LFB) and Hematoxylin/Eosin (H&E) staining and axonal damage assessed by immunohistochemical staining for SMI-32. Remyelination was evaluated by electron microscopy (EM) and calculation of g-ratios.ResultsJHMV-infected Cst7-/- mice were able to control viral replication within the CNS, indicating that cystatin F is not essential for an effective Th1 anti-viral immune response. Infiltration of T cells into the spinal cords of JHMV-infected Cst7-/- mice was increased compared to infected controls, and this correlated with increased axonal damage and demyelination associated with impaired remyelination. Single-cell RNA-seq of CD45 + cells enriched from spinal cords of infected Cst7-/- and control mice revealed enhanced expression of transcripts encoding T cell chemoattractants, Cxcl9 and Cxcl10, combined with elevated expression of interferon-g (Ifng) and perforin (Prf1) transcripts in CD8 + T cells from Cst7-/- mice compared to controls.ConclusionsCystatin F is not required for immune-mediated control of JHMV replication within the CNS. However, JHMV-infected Cst7-/- mice exhibited more severe clinical disease associated with increased demyelination and impaired remyelination. The increase in disease severity was associated with elevated expression of T cell chemoattractant chemokines, concurrent with increased neuroinflammation. These findings support the idea that cystatin F influences expression of proinflammatory gene expression impacting neuroinflammation, T cell activation and/or glia cell responses ultimately impacting neuroinflammation and neurologic disease.

Background: Blast-induced spinal cord injury (bSCI) is prevalent among military populations and frequently leads to irreversible spinal cord tissue damage that manifests as sensorimotor and autonomic nervous system dysfunction. Clinical recovery from bSCI has been proven to be multifactorial, as it is heavily dependent on the function of numerous cell populations in the tissue environment, as well as extensive ongoing inflammatory processes. This varied recovery process is thought to be due to irreversible spinal cord damage after 72 hours post-injury. Stem cell therapy for spinal cord injuries has long been investigated due to these cells' proliferative nature, ability to enhance neuro-regeneration, neuroprotection, remyelination of axons, and modulation of the immune and inflammatory responses. Therefore, this study hypothesizes that the impaired function after injury is due to a lack of specific ectoderm and neural stem cell population activity at the injury site. Methods: This study aimed to elucidate changes in endogenous stem cell patterns by evaluating immunohistochemical staining densities of various stem cell markers using a preclinical thoracolumbar bSCI model. Analysis was performed 24-, 48-, and 72 hours following blast exposure. Behavior tests to assess sensory and mechanical functions were also performed. Results: The following Cluster of differentiation (CD) markers CD105, CD45, CD133, and Vimentin, Nanog homebox (NANOG), and sex determining region Y HMG-box 2 (SOX2) positive cell populations were significantly elevated with trending increases in Octamerbinding transcription factor 4 (OCT4) in the thoracolumbar region of spinal cord tissue at 72 hours following bSCI (p < 0.05). Behavior analyses showed significant decreases in paw withdrawal thresholds in the hind limbs and changes in locomotion at 48- and 72 hours post-injury (p < 0.05). Conclusions: The significant increase in mesenchymal, pluripotent, and neural stem cell populations within the thoracolumbar region post-injury suggests that migratory patterns of stem cell populations are likely altered in response to bSCI. Behavioral deficits were consistent with those experienced by military personnel, such as increased pain-like behavior, reduced proprioception and coordination, and increased anxiety-like behavior post-bSCI, which underlines the translational capabilities of this model. While further research is vital to understand better the intrinsic and synergistic chemical and mechanical factors driving the migration of stem cells after traumatic injury, increased endogenous stem cell populations at the injury site indicate that stem cell-based treatments in patients suffering from bSCI could prove beneficial. [ABSTRACT FROM AUTHOR]

• Ligand-gated ion channel-linked receptor-mediated signaling affects neuronogenesis, neuronal and remyelination. • The roles of enzyme-linked receptors in CNS regeneration are basically consistent with their functions in nerve development. • There have already been molecular drugs targeting G-protein-coupled receptors for clinical treatment. Degenerative diseases and injuries of central nervous system (CNS) often cause nerve cell apoptosis and neural dysfunction. Protection of surviving cells or inducing the differentiation of stem cells into functional cells is considered to be an important way of neurorepair. In addition, transdifferentiation technology emerged recently is expected to provide new solutions for nerve regeneration. Cell surface receptors are transmembrane proteins embedded in cytoplasmic membrane, and play crucial roles in maintaining communication between extracellular signals and intracellular signaling processes. The extracellular microenvironment changed dramatically upon neural lesion, exploring the biological function of signals mediated by cell surface receptors will help to develop molecular strategies for nerve regeneration. An increasing number of studies have reported that cell surface receptor-mediated signaling affects the survival, differentiation, and functioning of neural cells, and even regulate their trans -lineage reprogramming. Here, we provide a review on the roles of cell surface receptors in CNS regeneration, thus providing new cues for better treatment of neurodegenerative diseases or nerve injury. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). In most patients, the disease starts with an acute onset followed by a remission phase, subsequent relapses and a later transition to steady chronic progression. In a minority of patients, this progressive phase develops from the beginning. MS relapses are characterized predominantly by the de novo formation of an inflammatory CNS lesion and the infiltration of immune cells, whereas the pathological features of MS progression include slowly expanding lesions, global brain atrophy and an inflammatory response predominantly mediated by macrophages/microglia. Importantly, this CNS-intrinsic pathophysiology appears to initiate early during the relapsing–remitting disease phase, while it turns into the key clinical MS feature in later stages. Currently approved disease-modifying treatments for MS are effective in modulating peripheral immunity by dampening immune cell activity or preventing the migration of immune cells into the CNS, resulting in the prevention of relapses; however, they show limited success in halting MS progression. In this manuscript, we first describe the pathological mechanisms of MS and summarize the approved therapeutics for MS progression. We also review the treatment options for progressive MS (PMS) that are currently under investigation. Finally, we discuss potential targets for novel treatment strategies in PMS. [ABSTRACT FROM AUTHOR]

Background: The myelin sheath ensures efficient nerve impulse transmission along the axons. Remyelination is a spontaneous process that restores axonal insulation, promoting neuroprotection and recovery after myelin damage. There is an urgent need for new pharmacological approaches to remyelination and to improve the most effective molecules. Some glucocorticoids (GC) were identified through phenotypical screens for their promyelinating properties. These GC compounds share the ability to bind the Smoothened (Smo) receptor of the Hedgehog (Hh) pathway. Gaining a deeper insight into how they modulate Smo receptor activity could guide structure-based studies to leverage the GCs' potent promyelinating activity for a more targeted approach to remyelination. Methods: Here we focused on clarifying the mechanism of action of Budesonide, a GC known to bind the Smo cysteine-rich domain (CRD) and prevent Smo translocation to the cilium in fibroblasts. Our study employed a combination of cellular, biochemical and molecular dynamics approaches. Results: We show that treating oligodendroglial cells with Budesonide promotes myelination of synthetic axons and reduces Smo CRD conformational flexibility. This inhibits the Smo-mediated canonical signaling while activating the Liver Kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, leading to Myelin basic protein (MBP) expression. Discussion: These insights pave the way for pharmacological targeting of Smo CRD to enhance oligodendrocyte precursor cells (OPCs) differentiation and improve remyelination. [ABSTRACT FROM AUTHOR]

Puerarin, a natural isoflavone, is commonly used as a Chinese herbal medicine for the treatment of various cardiovascular and neurological disorders. It has been found to be neuroprotective via TrK‐PI3K/Akt pathway, which is associated with anti‐inflammatory and antioxidant effects. Myelin damage in diseases such as multiple sclerosis (MS) and ischemia induces activation of endogenous oligodendrocyte progenitor cells (OPC) and subsequent remyelination by newly formed oligodendrocytes. It has been shown that human‐induced pluripotent stem cells (hiPSC)‐derived OPCs promote remyelination when transplanted to the brains of disease models. Here, we ask whether and how puerarin is beneficial to the generation of hiPSC‐derived OPCs and oligodendrocytes, and to the endogenous remyelination in mouse demyelination model. Our results show that puerarin increases the proportion of O4+ pre‐oligodendrocytes differentiated from iPSC‐derived neural stem cells. In vitro, puerarin increases proliferation of rat OPCs and enhances mitochondrial activity. Treatment of puerarin at progenitor stage increases the yielding of differentiated oligodendrocytes. In rat organotypic brain slice culture, puerarin promotes both myelination and remyelination. In vivo, puerarin increases oligodendrocyte repopulation during remyelination in mouse spinal cord following lysolethicin‐induced demyelination. Our findings suggest that puerarin promotes oligodendrocyte lineage progression and myelin repair, with a potential to be developed into therapeutic agent for neurological diseases associated with myelin damage. [ABSTRACT FROM AUTHOR]

Progressive multiple sclerosis (PMS) is an immune-initiated neurodegenerative condition that lacks effective therapies. Although peripheral immune infiltration is a hallmark of relapsing-remitting MS (RRMS), PMS is associated with chronic, tissue-restricted inflammation and disease-associated reactive glial states. The effector functions of disease-associated microglia, astrocytes, and oligodendrocyte lineage cells are beginning to be defined, and recent studies have made significant progress in uncovering their pathologic implications. In this review, we discuss the immune-glia interactions that underlie demyelination, failed remyelination, and neurodegeneration with a focus on PMS. We highlight the common and divergent immune mechanisms by which glial cells acquire disease-associated phenotypes. Finally, we discuss recent advances that have revealed promising novel therapeutic targets for the treatment of PMS and other neurodegenerative diseases. Progressive multiple sclerosis (PMS) is a neurodegenerative condition with chronic inflammation and glial cell pathology. In this review, Garton et al. discuss immune-glia interactions in PMS, highlighting potential therapeutic targets for PMS and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The precise neurophysiological changes prompted by meningeal lymphatic dysfunction remain unclear. Here, we showed that inducing meningeal lymphatic vessel ablation in adult mice led to gene expression changes in glial cells, followed by reductions in mature oligodendrocyte numbers and specific lipid species in the brain. These phenomena were accompanied by altered meningeal adaptive immunity and brain myeloid cell activation. During brain remyelination, meningeal lymphatic dysfunction provoked a state of immunosuppression that contributed to delayed spontaneous oligodendrocyte replenishment and axonal loss. The deficiencies in mature oligodendrocytes and neuroinflammation due to impaired meningeal lymphatic function were solely recapitulated in immunocompetent mice. Patients diagnosed with multiple sclerosis presented reduced vascular endothelial growth factor C in the cerebrospinal fluid, particularly shortly after clinical relapses, possibly indicative of poor meningeal lymphatic function. These data demonstrate that meningeal lymphatics regulate oligodendrocyte function and brain myelination, which might have implications for human demyelinating diseases. [Display omitted] • Meningeal lymphatic vessel ablation causes loss of mature oligodendrocytes • Demyelination due to meningeal lymphatic ablation relies on a competent immune system • Meningeal lymphatic dysfunction affects brain remyelination and aggravates axonal loss • Multiple sclerosis patients have decreased VEGF-C levels in their cerebrospinal fluid The neurophysiological processes regulated by meningeal lymphatic function remain unclear. das Neves et al. showed that meningeal lymphatic dysfunction leads to loss of mature oligodendrocytes and demyelination in the brain. Defective meningeal lymphatics incited a neuroinflammatory environment that limited oligodendrocyte replenishment after a demyelinating insult. This work might have therapeutic implications for the central nervous system demyelinating autoimmune disorders. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications FGF, VEGFR‐2 and CSF1R signalling pathways play a key role in the pathogenesis of multiple sclerosis (MS). Selective inhibition of FGFR by infigratinib in MOG35‐55‐induced experimental autoimmune encephalomyelitis (EAE) prevented severe first clinical episodes by 40%; inflammation and neurodegeneration were reduced, and remyelination was enhanced. Multi‐kinase inhibition of FGFR1‐3, CSFR and VEGFR‐2 by fexagratinib (formerly known as AZD4547) may be more efficient in reducing inflammation, neurodegeneration and regeneration in the disease model.Female C57BL/6J mice were treated with fexagratinib (6.25 or 12.5 mg·kg−1) orally or placebo over 10 days either from time of EAE induction (prevention experiment) or onset of symptoms (suppression experiment). Effects on inflammation, neurodegeneration and remyelination were assessed at the peak of the disease (Day 18/20 post immunization) and the chronic phase of EAE (Day 41/42).In the prevention experiment, treatment with 6.25 or 12.5 mg·kg−1 fexagratinib prevented severe first clinical episodes by 66.7% or 84.6% respectively. Mice treated with 12.5 mg·kg−1 fexagratinib hardly showed any symptoms in the chronic phase of EAE. In the suppression experiment, fexagratinib resulted in a long‐lasting reduction of severe symptoms by 91 or 100%. Inflammation and demyelination were reduced, and axonal density, numbers of oligodendrocytes and their precursor cells, and remyelinated axons were increased by both experimental approaches.Multi‐kinase inhibition by fexagratinib in a well‐tolerated dose of 1 mg·kg−1 in humans may be a promising approach to reduce inflammation and neurodegeneration, to slow down disease progression and support remyelination in patients. [ABSTRACT FROM AUTHOR]

Although treatment for multiple sclerosis (MS) has undergone a revolution in the last decades, at least two important barriers remain: alleviation of innate inflammation driving disease progression and promotion of remyelination and neural regeneration. Mesenchymal stem cells (MSCs) possess immunomodulatory properties and promote remyelination in murine MS models. The main therapeutic mechanism has, however, been attributed to their potent paracrine capacity, and not to in vivo tissue implantation. Studies have demonstrated that exosomes released as part of the cells' secretome effectively encapsulate the beneficial properties of MSCs. These membrane-enclosed nanoparticles contain a variety of proteins and nucleic acids and serve as mediators of intercellular communication. In vitro studies have demonstrated that exosomes from MSCs modulate activated microglia from an inflammatory to an anti-inflammatory phenotype and thereby dampen the innate inflammation. Rodent studies have also demonstrated potent immunomodulation and remyelination with improved outcomes following exosome administration. Thus, exosomes from MSCs may represent a potential cell-free treatment modality to prevent disease progression and promote remyelination in MS. In this narrative review, we summarize the current knowledge of exosomes from MSCs as a potential treatment for MS and discuss the remaining issues before successful translation into clinical trials. [ABSTRACT FROM AUTHOR]

Remyelination after white matter injury (WMI) often fails in diseases such as multiple sclerosis because of improper recruitment and repopulation of oligodendrocyte precursor cells (OPCs) in lesions. How OPCs elicit specific intracellular programs in response to a chemically and mechanically diverse environment to properly regenerate myelin remains unclear. OPCs construct primary cilia, specialized signaling compartments that transduce Hedgehog (Hh) and G-protein-coupled receptor (GPCR) signals. We investigated the role of primary cilia in the OPC response to WMI. Removing cilia from OPCs genetically via deletion of Ift88 results in OPCs failing to repopulate WMI lesions because of reduced proliferation. Interestingly, loss of cilia does not affect Hh signaling in OPCs or their responsiveness to Hh signals but instead leads to dysfunctional cyclic AMP (cAMP)-dependent cAMP response element-binding protein (CREB)-mediated transcription. Because inhibition of CREB activity in OPCs reduces proliferation, we propose that a GPCR/cAMP/CREB signaling axis initiated at OPC cilia orchestrates OPC proliferation during development and in response to WMI.

Abstract 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 damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy.

Abstract Background Multiple sclerosis (MS) is a chronic neurological condition and the leading cause of non-traumatic disability in young adults. MS pathogenesis leads to the death of oligodendrocytes, demyelination, and progressive central nervous system neurodegeneration. Endogenous remyelination occurs in people with MS (PwMS) but is insufficient to repair the damage. Our preclinical studies in mice indicate that endogenous remyelination can be supported by the delivery of repetitive transcranial magnetic stimulation (rTMS). Our phase I trial concluded that 20 sessions of rTMS, delivered over 5 weeks, are safe and feasible for PwMS. This phase II trial aims to investigate the safety and preliminary efficacy of rTMS for PwMS. Methods Participants must be aged 18–65 years, diagnosed with MS by a neurologist, stable and relapse free for 6 months, have an Extended Disability Status Scale (EDSS) between 1.5 and 6 (inclusive), willing to travel to a study site every weekday for 4 consecutive weeks, and able to provide informed consent and access the internet. Participants from multiple centres will be randomised 2:1 (rTMS to sham) stratified by sex. The intervention will be delivered with a Magstim Rapid2 stimulator device and circular 90-mm coil or MagVenture MagPro stimulator device with C100 circular coil, positioned to stimulate a broad area including frontal and parietal cortices. For the rTMS group, pulse intensity will be set at 18% (MagVenture) or 25% (Magstim) of maximum stimulator output (MSO), and rTMS applied as intermittent theta burst stimulation (iTBS) (~ 3 min per side; 600 pulses). For the sham group, the procedure will be the same, but the intensity is set at 0%. Each participant will attend 20 intervention sessions over a maximum of 5 weeks. Outcome measures include MS Functional Composite Score (primary), Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Quality of Life, and Pittsburgh Sleep Quality Index/Numeric Rating Scale and adverse events (secondary) and advanced MRI metrics (tertiary). Outcomes will be measured at baseline and after completing the intervention. Discussion This study will determine if rTMS can improve functional outcomes or other MS symptoms and determine whether rTMS has the potential to promote remyelination in PwMS. Trial registration Registered with Australian New Zealand Clinical Trials Registry, 20 January 2022; ACTRN12622000064707.

Multiple sclerosis (MS) is a complicated, inflammatory disease that causes demyelination of the central nervous system (CNS), resulting in a variety of neurological abnormalities. Over the past several decades, different animal models have been used to replicate the clinical symptoms and neuropathology of MS. The experimental model of experimental autoimmune/allergic encephalomyelitis (EAE) and viral and toxin-induced model was widely used to investigate the clinical implications of MS. Discoidin domain receptor 1 (DDR1) signaling in oligodendrocytes (OL) brings a new dimension to our understanding of MS pathophysiology. DDR1 is effectively involved in the OL during neurodevelopment and remyelination. It has been linked to many cellular processes, including migration, invasion, proliferation, differentiation, and adhesion. However, the exact functional involvement of DDR1 in developing OL and myelinogenesis in the CNS remains undefined. In this review, we critically evaluate the current literature on DDR1 signaling in OL and its proliferation, migration, differentiation, and myelination mechanism in OL in association with the progression of MS. It increases our knowledge of DDR1 in OL as a novel target molecule for oligodendrocyte-associated diseases in the CNS, including MS.

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 damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system (CNS). It is characterized by a heightened activation of the immune system with ensuing inflammation, demyelination and neurodegeneration with consequences such as motor, sensory, cognitive, as well as autonomic dysfunctions. While a range of immune-modulatory drugs have shown certain efficacy in alleviating pathology and symptoms, none of the currently available therapeutics regenerates the damaged CNS to restore function. There is emerging evidence for leukotrienes and leukotriene receptors being involved in the various aspects of the MS pathology including neuroinflammation and de/remyelination. Moreover, leukotriene receptor antagonists such as the asthma drug montelukast diminish inflammation and promote regeneration/remyelination. Indeed, montelukast has successfully been tested in animal models of MS and a recent retrospective case-control study suggests that montelukast treatment reduces relapses in patients with MS. Therefore, we propose montelukast as a therapeutic adjuvant to the standard immune-modulatory drugs with the potential to reduce pathology and promote structural and functional restoration. Here, we review the current knowledge on MS, its pathology, and on the potential of leukotriene receptor antagonists as therapeutics for MS. [ABSTRACT FROM AUTHOR]

Oligodendrocyte myelination and remyelination after injury are intricately regulated by various intrinsic and extrinsic factors, including transcriptional regulators. Among these, the zinc-finger protein ZFP488 is an oligodendrocyte-enriched transcriptional regulator that promotes oligodendrocyte differentiation in the developing neural tube and in oligodendroglial cell lines. However, the specific in vivo genetic requirements for ZFP488 during oligodendrocyte development and remyelination have not been defined. To address this gap, we generated a lineage-traceable ZFP488 knock-out mouse line, wherein an H2b-GFP reporter replaces the ZFP488-coding region. Using these mice of either sex, we examined the dynamics of ZFP488 expression from the endogenous promoter in the developing central nervous system (CNS). We observed a unique expression pattern in the oligodendrocyte lineage, with ZFP488 expression particularly enriched in differentiated oligodendrocytes. ZFP488 loss resulted in delayed myelination in the developing CNS and impaired remyelination after demyelinating injury in the brain. Integrated transcriptomic and genomic profiling further revealed that ZFP488 loss decreased the expression of myelination-associated genes but not oligodendrocyte progenitor-associated genes, suggesting that ZFP488 serves as a positive regulator of myelination by regulating maturation programs. Thus, our genetic loss-of-function study revealed that ZFP488 regulates a stage-dependent differentiation program that controls the timing of CNS myelination and remyelination. [ABSTRACT FROM AUTHOR]

Sphingosine 1‐phosphate (S1P) is a bioactive lipid of the sphingolipid family and plays a pivotal role in the mammalian nervous system. Indeed, S1P is a therapeutic target for treating demyelinating diseases such as multiple sclerosis. Being part of an interconnected sphingolipid metabolic network, the amount of S1P available for signalling is equilibrated between its synthetic (sphingosine kinases 1 and 2) and degradative (sphingosine 1‐phosphate lyase) enzymes. Once produced, S1P exerts its biological roles via signalling to a family of five G protein‐coupled S1P receptors 1–5 (S1PR1–5). Despite significant progress, the precise roles that S1P metabolism and downstream signalling play in regulating myelin formation and repair remain largely opaque and somewhat controversial. Genetic or pharmacological studies adopting various model systems identify that stimulating S1P‐S1PR signalling protects myelin‐forming oligodendrocytes after central nervous system (CNS) injury and attenuates demyelination in vivo. However, evidence to support its role in remyelination of the mammalian CNS is limited, although blocking S1P synthesis sheds light on the role of endogenous S1P in promoting CNS remyelination. This review focuses on summarising the current understanding of S1P in CNS myelin formation and repair, discussing the complexity of S1P–S1PR interaction and the underlying mechanism by which S1P biosynthesis and signalling regulates oligodendrocyte myelination in the healthy and injured mammalian CNS, raising new questions for future investigation. [ABSTRACT FROM AUTHOR]

The development of therapeutic strategies to reduce impairments following spinal cord injury (SCI) motivates an active area of research, because there are no effective therapies. One strategy is to address injury‐induced demyelination of spared axons by promoting endogenous or exogenous remyelination. However, previously, we showed that new myelin was not necessary to regain hindlimb stepping following moderate thoracic spinal cord contusion in 3‐month‐old mice. The present analysis investigated two potential mechanisms by which animals can re‐establish locomotion in the absence of remyelination: compensation through intact white matter and conduction through spared axons. We induced a severe contusion injury to reduce the spared white matter rim in the remyelination deficient model, with no differences in recovery between remyelination deficient animals and injured littermate controls. We investigated the nodal properties of the axons at the lesion and found that in the remyelination deficient model, axons express the Nav1.2 voltage‐gated sodium channel, a sub‐type not typically expressed at mature nodes of Ranvier. In a moderate contusion injury, conduction velocities through the lesions of remyelination deficient animals were similar to those in animals with the capacity to remyelinate after injury. Detailed gait analysis and kinematics reveal subtle differences between remyelination deficient animals and remyelination competent controls, but no worse deficits. It is possible that upregulation of Nav1.2 channels may contribute to establishing conduction through the lesion. This conduction could contribute to compensation and regained motor function in mouse models of SCI. Such compensatory mechanism may have implications for interpreting efficacy results for remyelinating interventions in mice and the development of therapies for improving recovery following SCI. [ABSTRACT FROM AUTHOR]

Myelinating oligodendrocytes arise from the stepwise differentiation of oligodendrocyte progenitor cells (OPCs). Approximately 5% of all adult brain cells are OPCs. Why would a mature brain need such a large number of OPCs? New myelination is possibly required for higher‐order functions such as cognition and learning. Additionally, this pool of OPCs represents a source of new oligodendrocytes to replace those lost during injury, inflammation, or in diseases such as multiple sclerosis (MS). How OPCs are instructed to differentiate into oligodendrocytes is poorly understood, and for reasons presently unclear, resident pools of OPCs are progressively less utilized in MS. The complement component 1, q subcomponent‐like (C1QL) protein family has been studied for their functions at neuron–neuron synapses, but we show that OPCs express C1ql1. We created OPC‐specific conditional knockout mice and show that C1QL1 deficiency reduces the differentiation of OPCs into oligodendrocytes and reduces myelin production during both development and recovery from cuprizone‐induced demyelination. In vivo over‐expression of C1QL1 causes the opposite phenotype: increased oligodendrocyte density and myelination during recovery from demyelination. We further used primary cultured OPCs to show that C1QL1 levels can bidirectionally regulate the extent of OPC differentiation in vitro. Our results suggest that C1QL1 may initiate a previously unrecognized signaling pathway to promote differentiation of OPCs into oligodendrocytes. This study has relevance for possible novel therapies for demyelinating diseases and may illuminate a previously undescribed mechanism to regulate the function of myelination in cognition and learning. [ABSTRACT FROM AUTHOR]

[Display omitted] • In the cuprizone-induced demyelination model, the absence of Olig2 was significantly linked to the failure of remyelination. • Exosomes specifically enriched with Olig2 protein were constructed by XPack technology. • Exosomes loaded with Olig2 can engulfed by OPCs and efficient promote cell differentiation. • Exosomes loaded with Olig2 alleviate the demyelination process and enhance remyelination. The research aims to study the therapeutic impact of HEK293-XPack-Olig2 cell-derived exosomes on remyelination of the corpus callosum in a cuprizone-induced demyelinating disease model. A lentiviral vector expressing Olig2 was constructed using XPack technology. The highly abundant Olig2 exosomes (ExoOs) were isolated by centrifugation for subsequent experiments. Western blot, nanoparticle tracking analysis (NTA), and electron microscopy showed no significant difference in particle size and morphology between Exos and ExoOs, and a high level of Olig2 expression could be detected in ExoOs, indicating that exosome modification by XPack technology was successful. The Black Gold/Fluromyelin staining analysis showed that the ExoOs group significantly reduced the demyelination area in the corpus callosum compared to the PBS and Exos groups. Additionally, the PDGFRα/APC staining of the demyelinating region revealed an increase in APC+ oligodendrocytes and a decrease in PDGFRα+ oligodendrocyte progenitor cells (OPCs) in the ExoOs group. Furthermore, there was evident myelin regeneration in the demyelinated areas after ExoOs treatment, with better g-ratio and a higher number of intact myelin compared to the other treatment groups. The level of Sox10 expression in the brain tissue of the ExoOs group were higher compared to those of the PBS and Exos groups. The demyelination process can be significantly slowed down by the XPack-modified exosomes, the differentiation of OPCs promoted, and myelin regeneration accelerated under pathological conditions. This process is presumed to be achieved by changing the expression level of intracellular differentiation-related genes after exosomes transport Olig2 enriched into oligodendrocyte progenitors. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a chronic neurological condition and the leading cause of non-traumatic disability in young adults. MS pathogenesis leads to the death of oligodendrocytes, demyelination, and progressive central nervous system neurodegeneration. Endogenous remyelination occurs in people with MS (PwMS) but is insufficient to repair the damage. Our preclinical studies in mice indicate that endogenous remyelination can be supported by the delivery of repetitive transcranial magnetic stimulation (rTMS). Our phase I trial concluded that 20 sessions of rTMS, delivered over 5 weeks, are safe and feasible for PwMS. This phase II trial aims to investigate the safety and preliminary efficacy of rTMS for PwMS. Methods: Participants must be aged 18–65 years, diagnosed with MS by a neurologist, stable and relapse free for 6 months, have an Extended Disability Status Scale (EDSS) between 1.5 and 6 (inclusive), willing to travel to a study site every weekday for 4 consecutive weeks, and able to provide informed consent and access the internet. Participants from multiple centres will be randomised 2:1 (rTMS to sham) stratified by sex. The intervention will be delivered with a Magstim Rapid2 stimulator device and circular 90-mm coil or MagVenture MagPro stimulator device with C100 circular coil, positioned to stimulate a broad area including frontal and parietal cortices. For the rTMS group, pulse intensity will be set at 18% (MagVenture) or 25% (Magstim) of maximum stimulator output (MSO), and rTMS applied as intermittent theta burst stimulation (iTBS) (~ 3 min per side; 600 pulses). For the sham group, the procedure will be the same, but the intensity is set at 0%. Each participant will attend 20 intervention sessions over a maximum of 5 weeks. Outcome measures include MS Functional Composite Score (primary), Fatigue Severity Scale, Hospital Anxiety and Depression Scale, Quality of Life, and Pittsburgh Sleep Quality Index/Numeric Rating Scale and adverse events (secondary) and advanced MRI metrics (tertiary). Outcomes will be measured at baseline and after completing the intervention. Discussion: This study will determine if rTMS can improve functional outcomes or other MS symptoms and determine whether rTMS has the potential to promote remyelination in PwMS. Trial registration: Registered with Australian New Zealand Clinical Trials Registry, 20 January 2022; ACTRN12622000064707. [ABSTRACT FROM AUTHOR]

Background and purpose: Pediatric multiple sclerosis (MS) displays different pathological features compared to adult MS, which can be studied in vivo by assessing tissue magnetic susceptibility with 3T‐MRI. We aimed to assess different white matter lesions (WMLs) phenotypes in pediatric MS patients using quantitative susceptibility mapping (QSM) and susceptibility mapping weighted imaging (SMWI) over 12 months. Methods: Eleven pediatric MS patients [female: 63.6%; mean ± standard deviation (SD) age and disease duration: 16.3 ± 2.2 and 2.4 ± 1.5; median (range) Expanded Disability Status Scale (EDSS) 1 (0‐2)] underwent 3 Tesla‐MRI exams and EDSS assessments at baseline and after 1 year. QSM and SMWI were obtained using 3‐dimensional (3D)‐segmented echo‐planar‐imaging with submillimetric spatial resolution. WMLs were classified according to their QSM appearance and SMWI was used to identify QSM hyperintensities ascribable to veins. Total brain volumes at baseline and follow‐up were computed using high‐resolution 3D T1‐weighted images. Results: Mean ± SD paramagnetic rim lesions (PRLs) prevalence was 7.0% ± 9.0. Fifty‐four percent (6/11) of patients exhibited at least one PRL, with one patient exhibiting ≥ 4 PRLs. All patients showed QSM‐iso‐/hypo‐intense lesions, which represented a mean ± SD of 65.8% ± 22.7 of total WMLs. QSM‐hyperintense WMLs showed a positive correlation with total brain volume reduction at follow‐up (r = 0.705; p =.02). No lesion was classified as different between baseline and follow‐up. Conclusion: Chronic compartmentalized inflammation seems to occur early in pediatric MS patients with short disease duration. A high prevalence of iso‐/hypo‐intense lesions was found, which could account for the higher remyelination potential in pediatric MS. [ABSTRACT FROM AUTHOR]

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 β‐galactosidase activity in O4+ late oligodendrocyte progenitor cells (OPCs). The senescent O4+/β‐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. [ABSTRACT FROM AUTHOR]

Even though several highly effective treatments have been developed for multiple sclerosis (MS), the underlying pathological mechanisms and drivers of the disease have not been fully elucidated. In recent years, there has been a growing interest in studying neuroinflammation in the context of glial cell involvement as there is increasing evidence of their central role in disease progression. Although glial cell communication and proper function underlies brain homeostasis and maintenance, their multiple effects in an MS brain remain complex and controversial. In this review, we aim to provide an overview of the contribution of glial cells, oligodendrocytes, astrocytes, and microglia in the pathology of MS during both the activation and orchestration of inflammatory mechanisms, as well as of their synergistic effects during the repair and restoration of function. Additionally, we discuss how the understanding of glial cell involvement in MS may provide new therapeutic targets either to limit disease progression or to facilitate repair. [ABSTRACT FROM AUTHOR]

Nuclear erythroid 2-related factor 2 (Nrf2) and its downstream effector heme oxygenase 1 (HO-1) are commonly activated in response to cellular stresses. The elevated expression of HO-1 has been associated with markedly accelerated peripheral nerve regeneration. This study aimed to evaluate the impact of a naturally occurring dietary Nrf2/HO-1 activator—sulforaphane (SFN)—on regeneration in a murine sciatic nerve crush model. The beneficial safety profile of SFN has been thoroughly investigated and confirmed several times. Here, SFN was administered daily, starting immediately after C57BL/6 mice were subjected to sciatic nerve crush injury. Injured sciatic nerves were excised at various time points post injury for molecular, immunohistochemical and morphometric analyses. Moreover, functional assessment was performed by grip strength analysis and electrophysiology. Following SFN treatment, the early response to injury includes a modulation of autophagic pathways and marked upregulation of Nrf2/HO-1 expression. This enhancement of HO-1 expression was maintained throughout the regeneration phase and accompanied by a significant increase in repair Schwann cells. In these cells, elevated proliferation rates were observed. Significant improvements in grip strength test performance, nerve conduction velocity and remyelination were also noted following SFN treatment. Collectively, SFN modulates cytoprotective and autophagic pathways in the injured nerve, increasing the number of repair Schwann cells and contributing to effective nerve regeneration. Given the availability of SFN as a nutritional supplement, this compound might constitute a novel regenerative approach with broad patient accessibility and further studies on this topic are warranted. [ABSTRACT FROM AUTHOR]

This editorial published in the journal Frontiers in Cellular Neuroscience discusses the significance of myelination and remyelination in the nervous system. Myelin, which surrounds nerve axons, is essential for proper nervous system development and function. Disruptions in myelination can lead to neurological deficits, but the nervous system has the ability to repair itself through remyelination. The editorial highlights recent advancements in neuroimaging and cellular biology that enhance our understanding of myelin dynamics and the potential for targeted interventions in neurological disorders. The article also explores the transcriptional control of myelination and remyelination in the central nervous system, emphasizing the importance of understanding these mechanisms for potential therapeutic interventions in demyelinating diseases. Additionally, another article mentioned in the editorial provides insights into the molecular and cellular processes involved in initial myelination in the central nervous system. These articles contribute to our understanding of the complex processes underlying myelination and offer potential avenues for further research and treatment development. [Extracted from the article]

Axons wrapped around the myelin sheath enable fast transmission of neuronal signals in the Central Nervous System (CNS). Unfortunately, myelin can be damaged by injury, viral infection, and inflammatory and neurodegenerative diseases. Remyelination is a spontaneous process that can restore nerve conductivity and thus movement and cognition after a demyelination event. Cumulative evidence indicates that remyelination can be pharmacologically stimulated, either by targeting natural inhibitors of Oligodendrocyte Precursor Cells (OPCs) differentiation or by reactivating quiescent Neural Stem Cells (qNSCs) proliferation and differentiation in myelinating Oligodendrocytes (OLs). Although promising results were obtained in animal models for demyelination diseases, none of the compounds identified have passed all the clinical stages. The significant number of patients who could benefit from remyelination therapies reinforces the urgent need to reassess drug selection approaches and develop strategies that effectively promote remyelination. Integrating Artificial Intelligence (AI)-driven technologies with patient-derived cell-based assays and organoid models is expected to lead to novel strategies and drug screening pipelines to achieve this goal. In this review, we explore the current literature on these technologies and their potential to enhance the identification of more effective drugs for clinical use in CNS remyelination therapies. [ABSTRACT FROM AUTHOR]

Background: Neuroplasticity as a mechanism to overcome central nervous system injury resulting from different neurological diseases has gained increasing attention in recent years. However, deficiency of these repair mechanisms leads to the accumulation of neuronal damage and therefore long-term disability. To date, the mechanisms by which remyelination occurs and why the extent of remyelination differs interindividually between multiple sclerosis patients regardless of the disease course are unclear. A member of the neurotrophins family, the brain-derived neurotrophic factor (BDNF) has received particular attention in this context as it is thought to play a central role in remyelination and thus neuroplasticity, neuroprotection, and memory. Objective: To analyse the current literature regarding BDNF in different areas of multiple sclerosis and to provide an overview of the current state of knowledge in this field. Conclusion: To date, studies assessing the role of BDNF in patients with multiple sclerosis remain inconclusive. However, there is emerging evidence for a beneficial effect of BDNF in multiple sclerosis, as studies reporting positive effects on clinical as well as MRI characteristics outweighed studies assuming detrimental effects of BDNF. Furthermore, studies regarding the Val66Met polymorphism have not conclusively determined whether this is a protective or harmful factor in multiple sclerosis, but again most studies hypothesized a protective effect through modulation of BDNF secretion and anti-inflammatory effects with different effects in healthy controls and patients with multiple sclerosis, possibly due to the pro-inflammatory milieu in patients with multiple sclerosis. Further studies with larger cohorts and longitudinal follow-ups are needed to improve our understanding of the effects of BDNF in the central nervous system, especially in the context of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored. This study assessed the therapeutic effect of ACT-1004-1239 in two demyelinating disease models. In the proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) model, ACT-1004-1239 administered upon the detection of the first signs of paralysis, resulted in a dose-dependent reduction in EAE disease severity, concomitant with diminished immune cell infiltrates in the CNS and reduced demyelination. Notably, efficacy correlated with elevated plasma concentrations of CXCL11 and CXCL12, two pharmacodynamic biomarkers of ACKR3 antagonism. Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. In the cuprizone-induced demyelination model, ACT-1004-1239 administered after 5 weeks of cuprizone exposure, significantly accelerated remyelination, already quantifiable one week after cuprizone withdrawal. Additionally, ACT-1004-1239 penetrated the CNS, elevating brain CXCL12 concentrations. These results demonstrate that ACKR3 antagonism significantly reduces the severity of experimental demyelinating diseases, even when treatment is initiated therapeutically, after the occurrence of lesions. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases. [ABSTRACT FROM AUTHOR]

Introduction: Excessive neuroinflammation, apoptosis, glial scar, and demyelination triggered by spinal cord injury (SCI) are major obstacles to SCI repair. Fucoidan, a natural marine plant extract, possesses broad‐spectrum anti‐inflammatory and immunomodulatory effects and is regarded as a potential therapeutic for various diseases, including neurological disorders. However, its role in SCI has not been investigated. Methods: In this study, we established an SCI model in mice and intervened in injury repair by daily intraperitoneal injections of different doses of fucoidan (10 and 20 mg/kg). Concurrently, primary oligodendrocyte precursor cells (OPCs) were treated in vitro to validate the differentiation‐promoting effect of fucoidan on OPCs. Basso Mouse Scale (BMS), Louisville Swim Scale (LSS), and Rotarod test were carried out to measure the functional recovery. Immunofluorescence staining, and transmission electron microscopy (TEM) were performed to assess the neuroinflammation, apoptosis, glial scar, and remyelination. Western blot analysis was conducted to clarify the underlying mechanism of remyelination. Results: Our results indicate that in the SCI model, fucoidan exhibits significant anti‐inflammatory effects and promotes the transformation of pro‐inflammatory M1‐type microglia/macrophages into anti‐inflammatory M2‐type ones. Fucoidan enhances the survival of neurons and axons in the injury area and improves remyelination. Additionally, fucoidan promotes OPCs differentiation into mature oligodendrocytes by activating the PI3K/AKT/mTOR pathway. Conclusion: Fucoidan improves SCI repair by modulating the microenvironment and promoting remyelination. [ABSTRACT FROM AUTHOR]

White matter injury (WMI) is thought to be a major contributor to long-term cognitive dysfunctions after traumatic brain injury (TBI). This damage occurs partly due to apoptotic death of oligodendrocyte lineage cells (OLCs) after the injury, triggered directly by the trauma or in response to degenerating axons. Recent research suggests that the gut microbiota modulates the inflammatory response through the regulation of peripheral immune cell infiltration after TBI. Additionally, T-cells directly impact OLCs differentiation and proliferation. Therefore, we hypothesized that the gut microbiota plays a critical role in regulating the OLC response to WMI influencing T-cells differentiation and activation. Gut microbial depletion early after TBI chronically reduced re-myelination, acutely decreased OLCs proliferation, and was associated with increased myelin debris accumulation. Surprisingly, the absence of T-cells in gut microbiota depleted mice restored OLC proliferation and remyelination after TBI. OLCs co-cultured with T-cells derived from gut microbiota depleted mice resulted in impaired proliferation and increased expression of MHC-II compared with T cells from control-injured mice. Furthermore, MHC-II expression in OLCs appears to be linked to impaired proliferation under gut microbiota depletion and TBI conditions. Collectively our data indicates that depletion of the gut microbiota after TBI impaired remyelination, reduced OLCs proliferation with concomitantly increased OLC MHCII expression, and required the presence of T cells. This data suggests that T cells are an important mechanistic link by which the gut microbiota modulate the oligodendrocyte response and white matter recovery after TBI. [ABSTRACT FROM AUTHOR]

Dysregulation of oligodendrocyte progenitor cell (OPC) recruitment and oligodendrocyte differentiation contribute to failure of remyelination in human demyelinating diseases such as multiple sclerosis (MS). Deletion of muscarinic receptor enhances OPC differentiation and remyelination. However, the role of ligand-dependent signaling versus constitutive receptor activation is unknown. We hypothesized that dysregulated acetylcholine (ACh) release upon demyelination contributes to ligand-mediated activation hindering myelin repair. Following chronic cuprizone (CPZ)-induced demyelination (male and female mice), we observed a 2.5-fold increase in ACh concentration. This increase in ACh concentration could be attributed to increased ACh synthesis or decreased acetylcholinesterase-/butyrylcholinesterase (BChE)-mediated degradation. Using choline acetyltransferase (ChAT) reporter mice, we identified increased ChAT-GFP expression following both lysolecithin and CPZ demyelination. ChAT-GFP expression was upregulated in a subset of injured and uninjured axons following intraspinal lysolecithin-induced demyelination. In CPZ-demyelinated corpus callosum, ChAT-GFP was observed in Gfap+ astrocytes and axons indicating the potential for neuronal and astrocytic ACh release. BChE expression was significantly decreased in the corpus callosum following CPZ demyelination. This decrease was due to the loss of myelinating oligodendrocytes which were the primary source of BChE. To determine the role of ligand-mediated muscarinic signaling following lysolecithin injection, we administered neostigmine, a cholinesterase inhibitor, to artificially raise ACh. We identified a dose-dependent decrease in mature oligodendrocyte density with no effect on OPC recruitment. Together, these results support a functional role of ligand-mediated activation of muscarinic receptors following demyelination and suggest that dysregulation of ACh homeostasis directly contributes to failure of remyelination in MS. [ABSTRACT FROM AUTHOR]

The Cambridge Centre for Myelin Repair One (CCMR-One) trial showed that 6 months of bexarotene reduces visual evoked potential (VEP) latency in people with relapsing-remitting multiple sclerosis (MS). In a single-centre follow-up study of these participants, we re-examined full-field VEP and clinical assessments. Twenty participants (12 bexarotene and 8 placebo) were seen on average 27 months after their trial involvement. In an analysis of all eyes with recordable signal (24 bexarotene and 14 placebo), the adjusted bexarotene-placebo treatment difference in P100 latency was −7.79 (95% confidence interval (CI) = −14.76, −0.82) ms, p = 0.044. We conclude that there were durable improvements in VEP latency, suggesting long-term benefits from exposure to a remyelinating drug. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complicated, inflammatory disease that causes demyelination of the central nervous system (CNS), resulting in a variety of neurological abnormalities. Over the past several decades, different animal models have been used to replicate the clinical symptoms and neuropathology of MS. The experimental model of experimental autoimmune/allergic encephalomyelitis (EAE) and viral and toxin-induced model was widely used to investigate the clinical implications of MS. Discoidin domain receptor 1 (DDR1) signaling in oligodendrocytes (OL) brings a new dimension to our understanding of MS pathophysiology. DDR1 is effectively involved in the OL during neurodevelopment and remyelination. It has been linked to many cellular processes, including migration, invasion, proliferation, differentiation, and adhesion. However, the exact functional involvement of DDR1 in developing OL and myelinogenesis in the CNS remains undefined. In this review, we critically evaluate the current literature on DDR1 signaling in OL and its proliferation, migration, differentiation, and myelination mechanism in OL in association with the progression of MS. It increases our knowledge of DDR1 in OL as a novel target molecule for oligodendrocyte-associated diseases in the CNS, including MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated central nervous system (CNS) disease characterized by demyelination resulting from oligodendrocyte loss and inflammation. Cuprizone (CPZ) administration experimentally replicates MS pattern-III lesions, generating an inflammatory response through microgliosis and astrogliosis. Potentially remyelinating agents include oligodeoxynucleotides (ODN) with a specific immunomodulatory sequence consisting of the active motif PyNTTTTGT. In this work, the remyelinating effects of ODN IMT504 were evaluated through immunohistochemistry and qPCR analyses in a rat CPZ-induced demyelination model. Subcutaneous IMT504 administration exacerbated the pro-inflammatory response to demyelination and accelerated the transition to an anti-inflammatory state. IMT504 reduced microgliosis in general and the number of phagocytic microglia in particular and expanded the population of oligodendroglial progenitor cells (OPCs), later reflected in an increase in mature oligodendrocytes. The intracranial injection of IMT504 and intravenous inoculation of IMT504-treated B lymphocytes rendered comparable results. Altogether, these findings unveil potentially beneficial properties of IMT504 in the regulation of neuroinflammation and oligodendrogenesis, which may aid the development of therapies for demyelinating diseases such as MS. [ABSTRACT FROM AUTHOR]

central nervous system (CNS) inflammation triggers activation of the integrated stress response (ISR). We previously reported that prolonging the ISR protects remyelinating oligodendrocytes and promotes remyelination in the presence of inflammation. However, the exact mechanisms through which this occurs remain unknown. Here, we investigated whether the ISR modulator Sephin1 in combination with the oligodendrocyte differentiation enhancing reagent bazedoxifene (BZA) is able to accelerate remyelination under inflammation, and the underlying mechanisms mediating this pathway. We find that the combined treatment of Sephin1 and BZA is sufficient to accelerate early-stage remyelination in mice with ectopic IFN-γ expression in the CNS. IFN-γ, which is a critical inflammatory cytokine in multiple sclerosis (MS), inhibits oligodendrocyte precursor cell (OPC) differentiation in culture and triggers a mild ISR. Mechanistically, we further show that BZA promotes OPC differentiation in the presence of IFN-γ, while Sephin1 enhances the IFN-γ-induced ISR by reducing protein synthesis and increasing RNA stress granule formation in differentiating oligodendrocytes. Finally, pharmacological suppression of the ISR blocks stress granule formation in vitro and partially lessens the beneficial effect of Sephin1 on disease progression in a mouse model of MS, experimental autoimmune encephalitis (EAE). Overall, our findings uncover distinct mechanisms of action of BZA and Sephin1 on oligodendrocyte lineage cells under inflammatory stress, suggesting that a combination therapy may effectively promote restoring neuronal function in MS patients.

White matter injuries (WMIs) are the leading cause of neurologic impairment in infants born premature. There are no treatment options available. The most common forms of WMIs in infants occur prior to the onset of normal myelination, making its pathophysiology distinctive, thus requiring a tailored approach to treatment. Neonates present a unique opportunity to repair WMIs due to a transient abundance of neural stem/progenitor cells (NSPCs) present in the germinal matrix with oligodendrogenic potential. We identified an endogenous oxysterol, 20-αHydroxycholesterol (20HC), in human maternal breast milk that induces oligodendrogenesis through a sonic hedgehog (shh), Gli-dependent mechanism. Following WMI in neonatal mice, injection of 20HC induced subventricular zone-derived oligodendrogenesis and improved myelination in the periventricular white matter, resulting in improved motor outcomes. Targeting the oligodendrogenic potential of postnatal NSPCs in neonates with WMIs may be further developed into a novel approach to mitigate this devastating complication of preterm birth.

BackgroundThe myelin sheath ensures efficient nerve impulse transmission along the axons. Remyelination is a spontaneous process that restores axonal insulation, promoting neuroprotection and recovery after myelin damage. There is an urgent need for new pharmacological approaches to remyelination and to improve the most effective molecules. Some glucocorticoids (GC) were identified through phenotypical screens for their promyelinating properties. These GC compounds share the ability to bind the Smoothened (Smo) receptor of the Hedgehog (Hh) pathway. Gaining a deeper insight into how they modulate Smo receptor activity could guide structure-based studies to leverage the GCs’ potent promyelinating activity for a more targeted approach to remyelination.MethodsHere we focused on clarifying the mechanism of action of Budesonide, a GC known to bind the Smo cysteine-rich domain (CRD) and prevent Smo translocation to the cilium in fibroblasts. Our study employed a combination of cellular, biochemical and molecular dynamics approaches.ResultsWe show that treating oligodendroglial cells with Budesonide promotes myelination of synthetic axons and reduces Smo CRD conformational flexibility. This inhibits the Smo-mediated canonical signaling while activating the Liver Kinase B1 (LKB1)/ AMP-activated protein kinase (AMPK) pathway, leading to Myelin basic protein (MBP) expression.DiscussionThese insights pave the way for pharmacological targeting of Smo CRD to enhance oligodendrocyte precursor cells (OPCs) differentiation and improve remyelination.

Myelin repair is an unrealized therapeutic goal in the treatment of multiple sclerosis (MS). Uncertainty remains about the optimal techniques for assessing therapeutic efficacy and imaging biomarkers are required to measure and corroborate myelin restoration. We analyzed myelin water fraction imaging from ReBUILD, a double-blind, randomized placebo-controlled (delayed treatment) remyelination trial, that showed a significant reduction in VEP latency in patients with MS. We focused on brain regions rich in myelin. Fifty MS subjects in two arms underwent 3T MRI at baseline and months 3 and 5. Half of the cohort was randomly assigned to receive treatment from baseline through 3 mo, whereas the other half received treatment from 3 mo to 5 mo post-baseline. We computed myelin water fraction changes occurring in normal-appearing white matter of corpus callosum, optic radiations, and corticospinal tracts. An increase in myelin water fraction was documented in the normal-appearing white matter of the corpus callosum, in correspondence with the administration of the remyelinating treatment clemastine. This study provides direct, biologically validated imaging-based evidence of medically induced myelin repair. Moreover, our work strongly suggests that significant myelin repair occurs outside of lesions. We therefore propose myelin water fraction within the normal-appearing white matter of the corpus callosum as a biomarker for clinical trials looking at remyelination.

Abstract Demyelination is generated in several nervous system illnesses. Developing strategies for effective clinical treatments requires the discovery of promyelinating drugs. Increased GABAergic signaling through γ-aminobutyric acid type A receptor (GABAAR) activation in oligodendrocytes has been proposed as a promyelinating condition. GABAAR expressed in oligodendroglia is strongly potentiated by n-butyl-β-carboline-3-carboxylate (β-CCB) compared to that in neurons. Here, mice were subjected to 0.3% cuprizone (CPZ) added in the food to induce central nervous system demyelination, a well-known model for multiple sclerosis. Then β-CCB (1 mg/Kg) was systemically administered to analyze the remyelination status in white and gray matter areas. Myelin content was evaluated using Black-Gold II (BGII) staining, immunofluorescence (IF), and magnetic resonance imaging (MRI). Evidence indicates that β-CCB treatment of CPZ-demyelinated animals promoted remyelination in several white matter structures, such as the fimbria, corpus callosum, internal capsule, and cerebellar peduncles. Moreover, using IF, it was observed that CPZ intake induced an increase in NG2+ and a decrease in CC1+ cell populations, alterations that were importantly retrieved by β-CCB treatment. Thus, the promyelinating character of β-CCB was confirmed in a generalized demyelination model, strengthening the idea that it has clinical potential as a therapeutic drug.

Abstract Background Cystatin F is a secreted lysosomal cysteine protease inhibitor that has been implicated in affecting the severity of demyelination and enhancing remyelination in pre-clinical models of immune-mediated demyelination. How cystatin F impacts neurologic disease severity following viral infection of the central nervous system (CNS) has not been well characterized and was the focus of this study. We used cystatin F null-mutant mice (Cst7-/-) with a well-established model of murine coronavirus-induced neurologic disease to evaluate the contributions of cystatin F in host defense, demyelination and remyelination. Methods Wildtype controls and Cst7-/- mice were intracranially (i.c.) infected with a sublethal dose of the neurotropic JHM strain of mouse hepatitis virus (JHMV), with disease progression and survival monitored daily. Viral plaque assays and qPCR were used to assess viral levels in CNS. Immune cell infiltration into the CNS and immune cell activation were determined by flow cytometry and 10X genomics chromium 3’ single cell RNA sequencing (scRNA-seq). Spinal cord demyelination was determined by luxol fast blue (LFB) and Hematoxylin/Eosin (H&E) staining and axonal damage assessed by immunohistochemical staining for SMI-32. Remyelination was evaluated by electron microscopy (EM) and calculation of g-ratios. Results JHMV-infected Cst7-/- mice were able to control viral replication within the CNS, indicating that cystatin F is not essential for an effective Th1 anti-viral immune response. Infiltration of T cells into the spinal cords of JHMV-infected Cst7-/- mice was increased compared to infected controls, and this correlated with increased axonal damage and demyelination associated with impaired remyelination. Single-cell RNA-seq of CD45 + cells enriched from spinal cords of infected Cst7-/- and control mice revealed enhanced expression of transcripts encoding T cell chemoattractants, Cxcl9 and Cxcl10, combined with elevated expression of interferon-g (Ifng) and perforin (Prf1) transcripts in CD8 + T cells from Cst7-/- mice compared to controls. Conclusions Cystatin F is not required for immune-mediated control of JHMV replication within the CNS. However, JHMV-infected Cst7-/- mice exhibited more severe clinical disease associated with increased demyelination and impaired remyelination. The increase in disease severity was associated with elevated expression of T cell chemoattractant chemokines, concurrent with increased neuroinflammation. These findings support the idea that cystatin F influences expression of proinflammatory gene expression impacting neuroinflammation, T cell activation and/or glia cell responses ultimately impacting neuroinflammation and neurologic disease.

Background: Current treatments for Multiple Sclerosis (MS) poorly address chronic innate neuroinflammation nor do they offer effective remyelination. The vagus nerve has a strong regulatory role in inflammation and Vagus Nerve Stimulation (VNS) has potential to affect both neuroinflammation and remyelination in MS. Objective: This study investigated the effects of VNS on demyelination and innate neuroinflammation in a validated MS rodent model. Methods: Lysolecithin (LPC) was injected in the corpus callosum (CC) of 46 Lewis rats, inducing a demyelinated lesion. 33/46 rats received continuously-cycled VNS (cVNS) or one-minute per day VNS (1minVNS) or sham VNS from 2 days before LPC-injection until perfusion at 3 days post-injection (dpi) (corresponding with a demyelinated lesion with peak inflammation). 13/46 rats received cVNS or sham from 2 days before LPC-injection until perfusion at 11 dpi (corresponding with a partial remyelinated lesion). Immunohistochemistry and proteomics analyses were performed to investigate the extend of demyelination and inflammation. Results: Immunohistochemistry showed that cVNS significantly reduced microglial and astrocytic activation in the lesion and lesion border, and significantly reduced the Olig2+ cell count at 3 dpi. Furthermore, cVNS significantly improved remyelination with 57.4 % versus sham at 11 dpi. Proteomic gene set enrichment analyses showed increased activation of (glutamatergic) synapse pathways in cVNS versus sham, most pronounced at 3 dpi. Conclusion: cVNS improved remyelination of an LPC-induced lesion. Possible mechanisms might include modulation of microglia and astrocyte activity, increased (glutamatergic) synapses and enhanced oligodendrocyte clearance after initial injury.