Animal Models Of Demyelination Research Articles

Nobiletin Induces Oligodendrocyte Lineage Precursor Cells in a Cuprizone-Administered Demyelination Animal Model

We investigated the effect of nobiletin on the oligodendroglial cell lineage in a cuprizone-induced demyelination animal model. Nobiletin, a polymethoxyflavone, was administered to the model animal for 3 consecutive weeks (50 mg/kg, intraperitoneally, 2 times/week). Immunohistochemical analysis of the corpus callosum and/or Western blotting analysis of brain extracts revealed that cuprizone administration reduced immunoreactivity for myelin-basic protein (MBP), a marker for mature oligodendrocytes, and increased immunoreactivity for platelet derived-growth factor receptor (PDGFR)-α, a marker for oligodendrocyte precursor cells (OPCs). Nobiletin treatment did not affect these changes in the cuprizone-fed mice. Nobiletin treatment, however, increased the immunoreactivity against proteolipid protein (PLP)/DM-20, a marker for mature oligodendrocytes, OPCs, and oligodendrocyte lineage precursor cells, and also augmented immunoreactivity against oligodendrocyte transcription factor 2 (olig2), a marker for OPCs and their precursor cells. These findings suggest that nobiletin promotes the production of oligodendrocyte lineage precursor cells in a demyelination animal model, and that nobiletin treatment might be suitable for individuals with demyelination diseases such as multiple sclerosis.

Glatiramer acetate guards against rapid memory decline during relapsing-remitting experimental autoimmune encephalomyelitis.

Cognitive decline presents a therapeutic challenge for patients with multiple sclerosis (MS), a disease characterized by recurrent autoimmune demyelination and by progressive CNS degeneration. Glatiramer acetate (GA, also known as Copolymer 1, Cop-1, or Copaxone), commonly used to treat MS, reduces the frequency of relapses; it has both anti-inflammatory and neuroprotective properties. However, clinical trials have not definitively shown that GA improves cognitive impairment during MS. Using an in vivo animal model of autoimmune demyelination, i.e., relapsing-remitting experimental autoimmune encephalomyelitis (EAE), we tested short-term memory in EAE mice (EAE), in EAE mice treated with GA for 10 days starting at the time of immunization (EAE + GA), and in age-matched healthy, naïve mice (Naïve). Short-term memory was assessed using the cross-maze test at 10, 20, and 30 days post-immunization (d.p.i.); data were analyzed at each time point and over time. At 10 d.p.i., EAE and EAE + GA mice had better memory function than Naïve mice. However, at the later time points, EAE mice had a steep negative slope of memory function (indicating decline), whereas EAE + GA mice had a flatter, less-negative slope of memory function. Notably, the memory function of EAE mice significantly decreased over time compared with that of Naïve mice, indicating that EAE had a negative impact on cognitive ability. In contrast, there was no statistically significant difference between the slopes of memory function in mice with EAE treated with GA versus Naïve mice, which revealed effective, albeit partial, protection by GA treatment against progressive memory decline during EAE disease. Of particular interest, although EAE mice had memory decline over 30 d.p.i., their clinical disease scores improved during that time. Thus, our results suggest that EAE mice had a significant progressive memory decline and that GA, administered at the time of immunization, partially guards against rapid memory decline.

Characterizing oligodendrocyte lineage cell function by flow cytometry in animal models of demyelination

Characterizing oligodendrocyte lineage cell function by flow cytometry in animal models of demyelination

Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex.

Multiple Sclerosis affects mainly women and consists in intermittent or chronic damages to the myelin sheaths, focal inflammation, and axonal degeneration. Current therapies are limited to immunomodulators and antiinflammatory drugs, but there is no efficient treatment for stimulating the endogenous capacity of myelin repair. Progesterone and synthetic progestins have been shown in animal models of demyelination to attenuate myelin loss, reduce clinical symptoms severity, modulate inflammatory responses and partially reverse the age-dependent decline in remyelination. Moreover, progesterone has been demonstrated to promote myelin formation in organotypic cultures of cerebellar slices. In the present study, we show that progesterone and the synthetic 19-nor-progesterone derivative Nestorone® promote the repair of severe chronic demyelinating lesions induced by feeding cuprizone to female mice for up to 12 weeks. Progesterone and Nestorone increase the density of NG2(+) oligodendrocyte progenitor cells and CA II(+) mature oligodendrocytes and enhance the formation of myelin basic protein (MBP)- and proteolipid protein (PLP)-immunoreactive myelin. However, while demyelination in response to cuprizone was less marked in corpus callosum than in cerebral cortex, remyelination appeared earlier in the former. The remyelinating effect of progesterone was progesterone receptor (PR)-dependent, as it was absent in PR-knockout mice. Progesterone and Nestorone also decreased (but did not suppress) neuroinflammatory responses, specifically astrocyte and microglial cell activation. Therefore, some progestogens are promising therapeutic candidates for promoting the regeneration of myelin.

Direct visualization of membrane architecture of myelinating cells in transgenic mice expressing membrane-anchored EGFP.

Myelinogenesis is a complex process that involves substantial and dynamic changes in plasma membrane architecture and myelin interaction with axons. Highly ramified processes of oligodendrocytes in the central nervous system (CNS) make axonal contact and then extrapolate to wrap around axons and form multilayer compact myelin sheathes. Currently, the mechanisms governing myelin sheath assembly and axon selection by myelinating cells are not fully understood. Here, we generated a transgenic mouse line expressing the membrane-anchored green fluorescent protein (mEGFP) in myelinating cells, which allow live imaging of details of myelinogenesis and cellular behaviors in the nervous systems. mEGFP expression is driven by the promoter of 2'-3'-cyclic nucleotide 3'-phosphodiesterase (CNP) that is expressed in the myelinating cell lineage. Robust mEGFP signals appear in the membrane processes of oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system (PNS), wherein mEGFP expression defines the inner layers of myelin sheaths and Schmidt-Lanterman incisures in adult sciatic nerves. In addition, mEGFP expression can be used to track the extent of remyelination after demyelinating injury in a toxin-induced demyelination animal model. Taken together, the membrane-anchored mEGFP expression in the new transgenic line would facilitate direct visualization of dynamic myelin membrane formation and assembly during development and process remodeling during remyelination after various demyelinating injuries.

Interferon regulatory factor (IRF) 3 is critical for the development of experimental autoimmune encephalomyelitis.

BackgroundExperimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune inflammatory demyelination that is mediated by Th1 and Th17 cells. The transcription factor interferon regulatory factor 3 (IRF3) is activated by pathogen recognition receptors and induces interferon-β production.MethodsTo determine the role of IRF3 in autoimmune inflammation, we immunised wild-type (WT) and irf3−/− mice to induce EAE. Splenocytes from WT and irf3−/− mice were also activated in vitro in Th17-polarising conditions.ResultsClinical signs of disease were significantly lower in mice lacking IRF3, with reduced Th1 and Th17 cells in the central nervous system. Peripheral T-cell responses were also diminished, including impaired proliferation and Th17 development in irf3−/− mice. Myelin-reactive CD4+ cells lacking IRF3 completely failed to transfer EAE in Th17-polarised models as did WT cells transferred into irf3−/− recipients. Furthermore, IRF3 deficiency in non-CD4+ cells conferred impairment of Th17 development in antigen-activated cultures.ConclusionThese data show that IRF3 plays a crucial role in development of Th17 responses and EAE and warrants investigation in human multiple sclerosis.

Inhibitors of myelination: ECM changes, CSPGs and PTPs

After inflammation-induced demyelination, such as in the disease multiple sclerosis, endogenous remyelination often fails. However, in animal models of demyelination induced with toxins, remyelination can be quite robust. A significant difference between inflammation-induced and toxin-induced demyelination is the response of local cells within the lesion, including astrocytes, oligodendrocytes, microglia/macrophages, and NG2+ cells, which respond to inflammatory stimuli with increased extracellular matrix (ECM) protein and chondroitin sulfate proteoglycan (CSPG) production and deposition. Here, we summarize current knowledge of ECM changes in demyelinating lesions, as well as oligodendrocyte responses to aberrant ECM proteins and CSPGs after various types of demyelinating insults. The discovery that CSPGs act through the receptor protein tyrosine phosphatase sigma (PTPσ) and the Rho-ROCK pathway to inhibit oligodendrocyte process extension and myelination, but not oligodendrocyte differentiation (Pendleton et al., Experimental Neurology (2013) vol. 247, pp. 113–121), highlights the need to better understand the ECM changes that accompany demyelination and their influence on oligodendrocytes and effective remyelination.

Alterations of brain eicosanoid synthetic pathway in multiple sclerosis and in animal models of demyelination: Role of cyclooxygenase-2

Inflammation is a physiological response to exogenous and endogenous stimuli and, together with demyelination and immune system activation, is one of the key features of multiple sclerosis (MS). Arachidonic acid (AA) metabolism by cyclooxygenase (COX) and lipoxygenase (LO) enzymes leads to the production of proinflammatory eicosanoids, and stimulates cytokine production and activation of microglia and astrocytes, thereby contributing to MS pathology. Current therapies target the immune system but do not specifically target AA-related inflammatory pathway. Corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are frequently associated with immunomodulatory therapies to treat flu-like adverse effects. Few clinical and mounting preclinical data in MS show that AA metabolism contributes to immune system activation, demyelination and motor disabilities, and administration of NSAIDs reduces these symptoms. The beneficial effect of NSAIDs seems to be a prerogative of COX-2 selective inhibitors and suggests that NSAIDs selective for COX-2 may be more effective than mixed COX-1/2 inhibitors.

Quantitative MRI and ultrastructural examination of the cuprizone mouse model of demyelination

The cuprizone mouse model of demyelination was used to investigate the influence that white matter changes have on different magnetic resonance imaging results. In vivo T2 -weighted and magnetization transfer images (MTIs) were acquired weekly in control (n = 5) and cuprizone-fed (n = 5) mice, with significant increases in signal intensity in T2 -weighted images (p < 0.001) and lower magnetization transfer ratio (p < 0.001) in the corpus callosum of the cuprizone-fed mice starting at 3 weeks and peaking at 4 and 5 weeks, respectively. Diffusion tensor imaging (DTI), quantitative MTI (qMTI), and T1/T2 measurements were used to analyze freshly excised tissue after 6 weeks of cuprizone administration. In multicomponent T2 analysis with 10 ms echo spacing, there was no visible myelin water component associated with the short T2 value. Quantitative MTI metrics showed significant differences in the corpus callosum and external capsule of the cuprizone-fed mice, similar to previous studies of multiple sclerosis in humans and animal models of demyelination. Fractional anisotropy was significantly lower and mean, axial, and radial diffusivity were significantly higher in the cuprizone-fed mice. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: T1 versus the myelinated axon fraction (ρ = -0.90), the bound pool fraction (ƒ) versus the myelin sheath fraction (ρ = 0.93), and axial diffusivity versus the non-myelinated cell fraction (ρ = 0.92). Using Pearson's correlation coefficient, ƒ was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37ƒ - 0.25). Of the calculated MRI metrics, ƒ was the strongest indicator of myelin content, while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure.

Generation of demyelination models by targeted ablation of oligodendrocytes in the zebrafish CNS.

Demyelination is the pathological process by which myelin sheaths are lost from around axons, and is usually caused by a direct insult targeted at the oligodendrocytes in the vertebrate central nervous system (CNS). A demyelinated CNS is usually remyelinated by a population of oligodendrocyte progenitor cells, which are widely distributed throughout the adult CNS. However, myelin disruption and remyelination failure affect the normal function of the nervous system, causing human diseases such as multiple sclerosis. In spite of numerous studies aimed at understanding the remyelination process, many questions still remain unanswered. Therefore, to study remyelination mechanisms in vivo, a demyelination animal model was generated using a transgenic zebrafish system in which oligodendrocytes are conditionally ablated in the larval and adult CNS. In this transgenic system, bacterial nitroreductase enzyme (NTR), which converts the prodrug metronidazole (Mtz) into a cytotoxic DNA cross-linking agent, is expressed in oligodendrocyte lineage cells under the control of the mbp and sox10 promoter. Exposure of transgenic zebrafish to Mtz-containing media resulted in rapid ablation of oligodendrocytes and CNS demyelination within 48 h, but removal of Mtz medium led to efficient remyelination of the demyelinated CNS within 7 days. In addition, the demyelination and remyelination processes could be easily observed in living transgenic zebrafish by detecting the fluorescent protein, mCherry, indicating that this transgenic system can be used as a valuable animal model to study the remyelination process in vivo, and to conduct high-throughput primary screens for new drugs that facilitate remyelination.

Regulation of oligodendrocyte precursor migration during development, in adulthood and in pathology.

Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS). These cells originate from oligodendrocyte precursor cells (OPCs) during development, and they migrate extensively from oligodendrogliogenic niches along the neural tube to colonise the entire CNS. Like many other such events, this migratory process is precisely regulated by a battery of positional and signalling cues that act via their corresponding receptors and that are expressed dynamically by OPCs. Here, we will review the cellular and molecular basis of this important event during embryonic and postnatal development, and we will discuss the relevance of the substantial number of OPCs existing in the adult CNS. Similarly, we will consider the behaviour of OPCs in normal and pathological conditions, especially in animal models of demyelination and of the demyelinating disease, multiple sclerosis. The spontaneous remyelination observed after damage in demyelinating pathologies has a limited effect. Understanding the cellular and molecular mechanisms underlying the biology of OPCs, particularly adult OPCs, should help in the design of neuroregenerative strategies to combat multiple sclerosis and other demyelinating diseases.

Stressed cybrids model demyelinated axons in multiple sclerosis

Multiple sclerosis is likely caused by a complex interaction of multiple genes and environmental factors. The contribution of mitochondrial DNA genetic backgrounds has been frequently reported. To evaluate the effect of mitochondrial DNA haplogroups in the same genetic and environmental circumstances, we have built human transmitochondrial cell lines and simulated the effect of axon demyelination, one of the hallmarks of multiple sclerosis pathology, by altering the ionic gradients through the plasmalemma and increasing ATP consumption. In this model, mitochondrial biogenesis is observed. This process is larger in Uk cybrids, which mirrors their lower oxidative phosphorylation capacity in basal conditions. This model replicates a process occurring in both patients suffering from multiple sclerosis and several animal models of axon demyelination. Therefore, it can be used to analyze the contribution of various mitochondrial DNA genotypes to multiple sclerosis. In this sense, a longer or stronger energy stress, such as that associated with demyelinated axons in multiple sclerosis, could make Uk individuals more susceptible to this pathology. Finally, pharmacologic compounds targeted to mitochondrial biogenesis could be a potential therapy for multiple sclerosis.

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit

Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice.

ObjectiveConsidering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG112 promotes remyelination and improves functional recovery in lysolecithin induced focal demyelination in the white matter of spinal cord in mice.MethodsA focal demyelination model was created by stereotaxically injecting lysolecithin into the bilateral ventrolateral funiculus (VLF) of T8 and T9 mouse spinal cords. Immediately after lysolecithin injection mice were treated with COG112, prefix peptide control or vehicle control for 21 days. The locomotor function of the mice was measured by the beam walking test and Basso Mouse Scale (BMS) assessment. The nerve transmission of the VLF of mice was assessed in vivo by transcranial magnetic motor evoked potentials (tcMMEPs). The histological changes were also examined by by eriochrome cyanine staining, immunohistochemistry staining and electron microscopy (EM) method.ResultsThe area of demyelination in the spinal cord was significantly reduced in the COG112 group. EM examination showed that treatment with COG112 increased the thickness of myelin sheaths and the numbers of surviving axons in the lesion epicenter. Locomotor function was improved in COG112 treated animals when measured by the beam walking test and BMS assessment compared to controls. TcMMEPs also demonstrated the COG112-mediated enhancement of amplitude of evoked responses.ConclusionThe apoE-mimetic COG112 demonstrates a favorable combination of activities in suppressing inflammatory response, mitigating demyelination and in promoting remyelination and associated functional recovery in animal model of CNS demyelination. These data support that apoE-mimetic strategy may represent a promising therapy for MS and other demyelination disorders.

Chondroitin sulfate proteoglycans in demyelinated lesions impair remyelination

Failure of remyelination is a critical impediment to recovery in multiple sclerosis (MS). Chondroitin sulfate proteoglycans (CSPGs) have been reported to accumulate in MS lesions, and we thus examined the functional roles of CSPGs on oligodendrocyte precursor cells (OPCs), oligodendrocytes, and remyelination. We evaluated the expression of CSPGs in lysolecithin-injected mouse spinal cord, an animal model of demyelination and spontaneous remyelination. The functional impact of CSPGs on OPCs and remyelination was investigated using cultured adult murine and human OPCs and by treating demyelinated mice with xyloside to reduce the CSPG deposition that occurred following injury. Early and robust upregulation of CSPGs following lysolecithin-induced demyelination was cleared during remyelination. In culture, CSPGs anchored onto the substratum reduced the adhesion of mouse and human OPCs and their subsequent morphological differentiation into process-bearing oligodendrocytes. Soluble CSPGs added to already adherent OPCs reduced the development of processes, whereas the acquisition of mature myelin proteins was unimpeded. Stripe assays of alternating CSPG and control substrata confirmed the nonpermissive nature of CSPGs for OPC adhesion and morphological differentiation. Enzymatic degradation of CSPGs with chondroitinase ABC was sufficient to overcome CSPG-dependent inhibition of human oligodendrocytes. Finally, in vivo xyloside treatment to reduce CSPG synthesis in lysolecithin-demyelinated mice increased numbers of OPCs and oligodendrocytes in lesions, and culminated in improved remyelination. These results identify CSPGs as a nonpermissive substrate for OPCs and oligodendrocytes, and as a prominent impediment to remyelination. The data suggest the requirement for the neutralization of CSPGs for repair after demyelination.

Prolactin in multiple sclerosis

Multiple sclerosis (MS) is more common among women than men. MS often goes into remission during pregnancy, when prolactin (PRL) levels are known to be high. In an animal model of demyelination, PRL promoted myelin repair, suggesting it has potential as a remyelinating therapy in MS. In this systematic review, we examined the known associations between PRL and MS, in order to elucidate its potential role in the pathophysiology and treatment of MS. A systematic search was performed in the electronic databases PubMed and EMBASE, using the keywords "prolactin" AND “multiple sclerosis.” The inclusion criteria were met by 23 studies. These studies suggested to us that elevated PRL may be more common in MS patients than in controls. Hyperprolactinemia may also be associated with clinical relapse in MS, especially among patients with hypothalamic lesions or optic neuritis; however, it is unknown if this is a cause or consequence of a relapse. Overall, most people with MS have normal PRL levels. The impact of PRL on MS outcomes remains unclear.

IFN-γ-induced apoptosis of human embryonic stem cell derived oligodendrocyte progenitor cells is restricted by CXCR2 signaling

Engraftment of human embryonic stem cell (hESC)-derived OPCs in animal models of demyelination results in remyelination and clinical recovery, supporting the feasibility of cell replacement therapies in promoting repair of damaged neural tissue. A critical gap in our understanding of the mechanisms associated with repair revolves around the effects of the local microenvironment on transplanted cell survival. We have determined that treatment of human ESC-derived OPCs with the pleiotropic cytokine IFN-γ promotes apoptosis that is associated with mitochondrial cytochrome c released into the cytosol with subsequent caspase 3 activation. IFN-γ-induced apoptosis is mediated, in part, by secretion of the CXC chemokine ligand 10 (CXCL10) from IFN-γ-treated cells. Signaling through the chemokine receptor CXCR2 by the ligand CXCL1 functions in a tonic manner by muting apoptosis and this is associated with reduced levels of cytosolic cytochrome c and impaired cleavage of caspase 3. These findings support a role for both IFN-γ and CXCL10 in contributing to neuropathology by promoting OPC apoptosis. In addition, these data suggest that hOPCs used for therapeutic treatment for human neurologic disease/damage are susceptible to death through exposure to local inflammatory cytokines present within the inflammatory milieu.

Myelin debris regulates inflammatory responses in an experimental demyelination animal model and multiple sclerosis lesions

In multiple sclerosis (MS), gray matter pathology is characterized by less pronounced inflammation when compared with white matter lesions. Although regional differences in the cytoarchitecture may account for these differences, the amount of myelin debris in the cortex during a demyelinating event might also be contributory. To analyze the association between myelin debris levels and inflammatory responses, cortical areas with distinct and sparse myelination were analyzed for micro- and astrogliosis before and after cuprizone-induced demyelination in mice. In postmortem tissue of MS patients, leucocortical lesions were assessed for the type and level of inflammation in the cortical and white matter regions of the lesion. Furthermore, mice were injected intracerebrally with myelin-enriched debris, and the inflammatory response analyzed in white and grey matter areas. Our studies show that the magnitude of myelin loss positively correlates with microgliosis in the cuprizone model. In MS, the number of MHC class II expressing cells is higher in the white compared with the grey matter part of leucocortical lesions. Finally, direct application of myelin debris into the corpus callosum or cortex of mice induces profound and comparable inflammation in both regions. Our data suggest that myelin debris is an important variable in the inflammatory response during demyelinating events. Whether myelin-driven inflammation affects neuronal integrity remains to be clarified.

The T3-induced gene KLF9 regulates oligodendrocyte differentiation and myelin regeneration

Hypothyroidism is a well-described cause of hypomyelination. In addition, thyroid hormone (T3) has recently been shown to enhance remyelination in various animal models of CNS demyelination. What are the ways in which T3 promotes the development and regeneration of healthy myelin? To begin to understand the mechanisms by which T3 drives myelination, we have identified genes regulated specifically by T3 in purified oligodendrocyte precursor cells (OPCs). Among the genes identified by genomic expression analyses were four transcription factors, Kruppel-like factor 9 (KLF9), basic helix-loop-helix family member e22 (BHLHe22), Hairless (Hr), and Albumin D box-binding protein (DBP), all of which were induced in OPCs by both brief and long term exposure to T3. To begin to investigate the role of these genes in myelination, we focused on the most rapidly and robustly induced of these, KLF9, and found it is both necessary and sufficient to promote oligodendrocyte differentiation in vitro. Surprisingly, we found that loss of KLF9 in vivo negligibly affects the formation of CNS myelin during development, but does significantly delay remyelination in cuprizone-induced demyelinated lesions. These experiments indicate that KLF9 is likely a novel integral component of the T3-driven signaling cascade that promotes the regeneration of lost myelin. Future analyses of the roles of KLF9 and other identified T3-induced genes in myelination may lead to novel insights into how to enhance the regeneration of myelin in demyelinating diseases such as multiple sclerosis.

Background and rationale for mechanism of action, efficacy, and safety of fingolimod (Gilenya), the first oral therapy for remitting-relapsing multiple sclerosis

Background and rationale for mechanism of action, efficacy, and safety of fingolimod (Gilenya), the first oral therapy for remitting-relapsing multiple sclerosis