Tellurium-induced neuropathy: a model for reversible reductions in myelin protein gene expression.

Inclusion of 1.1% tellurium in the diet of developing rats causes a highly synchronous primary demyelination of peripheral nerves, which is followed closely by a period of rapid remyelination. The demyelination is related to the inhibition of squalene epoxidase activity, which results in a block in cholesterol synthesis and accumulation of squalene. We now report that the demyelination resulting from this limiting of the supply of an intrinsic component of myelin (cholesterol) leads to repression of the expression of mRNA for myelin-specific proteins. Tellurium exposure resulted in an increase in total RNA (largely rRNA) in sciatic nerve, which could not be accounted for by cellular proliferation; these increased levels of rRNA may be a reactive response of Schwann cells to toxic insult and may relate to the higher levels of protein synthesis required during remyelination. In contrast, steady-state levels of mRNA, determined by Northern blot analysis, for P0 and myelin basic protein were markedly decreased (levels after 5 days of tellurium exposure were only 10-15% of control levels as a fraction of total RNA and 25-35% of control levels when the increased levels of total RNA were taken into account). Message levels increased during the subsequent period of remyelination and reached near-normal levels 30 days after beginning tellurium exposure. Although message levels for the myelin-associated glycoprotein showed a similar temporal pattern, levels did not decrease as greatly and subsequently increased sooner than did levels for P0 and myelin basic protein. The coordinate alterations in message levels for myelin proteins indicate that Schwann cells can down-regulate and then up-regulate the synthesis of myelin in response to alterations in the supply of membrane components.     

Noninvasive detection of cuprizone induced axonal damage and demyelination in the mouse corpus callosum

Previously, we tested the prediction that axonal damage results in decreased axial diffusivity (λ_∥) while demyelination leads to increased radial diffusivity (λ_?). Cuprizone treatment of C57BL/6 mice was a highly reproducible model of CNS white matter demyelination and remyelination affecting the corpus callosum (CC). In the present study, six C57BL/6 male mice were fed 0.2% cuprizone for 12 weeks followed by 12 weeks of recovery on normal chow. The control mice were fed normal chow and imaged in parallel. Biweekly in vivo DTI examinations showed transient decrease of λ_∥ in CC at 2–6 weeks of cuprizone treatment. Immunostaining for nonphosphorylated neurofilaments demonstrated corresponding axonal damage at 4 weeks of treatment. Significant demyelination was evident from loss of Luxol fast blue staining at 6–12 weeks of cuprizone ingestion and was paralleled by increased λ_? values, followed by partial normalization during the remyelination phase. The sensitivity of λ_? to detect demyelination may be modulated in the presence of axonal damage during the early stage of demyelination at 4 weeks of cuprizone treatment. Our results suggest that λ_∥ and λ_? may be useful in vivo surrogate markers of axonal and myelin damage in mouse CNS white matter. Magn Reson Med, 2006. Published 2006 Wiley‐Liss, Inc.     

Deficient arginase II expression without alteration in arginase I expression attenuated experimental autoimmune encephalomyelitis in mice

In the past there have been a multitude of studies that ardently support the role of arginase II (Arg II) in vascular and endothelial disorders; however, the regulation and function of Arg II in autoimmune diseases has thus far remained unclear. Here we report that a global Arg II null mutation in mice suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. During EAE, both Arg I and Arg II were induced in spinal cords, but only Arg II was induced in spleens and splenic dendritic cells (DCs). DC activation by lipopolysaccharide (LPS), CD40L or TLR8 agonist significantly enhanced Arg II expression without affecting Arg I expression. Conversely, DC differentiating cytokines [IL‐4 and granulocyte macrophage‐colony‐stimulating factor (GM‐CSF)] yielded opposite effects. In addition, Arg I and Arg II were regulated differentially during Th1 and Th17 cell polarization. Arg II deficiency in mice delayed EAE onset, ameliorated clinical symptoms and reduced myelin loss, accompanied by a remarkable reduction in the EAE‐induced spinal cord expression of Th17 cell markers (IL‐17 and RORγt). The abundance of Th17 cells and IL‐23⁺ cells in relevant draining lymph nodes was significantly reduced in Arg II knockout mice. In activated DCs, Arg II deficiency significantly suppressed the expression of Th17‐differentiating cytokines IL‐23 and IL‐6. Interestingly, Arg II deficiency did not lead to any compensatory increase in Arg I expression in vivo and in vitro. In conclusion, Arg II was identified as a factor promoting EAE likely via an Arg I‐independent mechanism. Arg II may promote EAE by enhancing DC production of Th17‐differentiating cytokines. Specific inhibition of Arg II could be a potential therapy for multiple sclerosis.     

Varicella‐zoster virus encephalomyelitis with a prominent demyelinating component

The histopathologic presentation of varicella‐zoster virus (VZV) infection of the central nervous system is varied and is not well understood. Here we report a case of VZV encephalomyelitis with prominent demyelinating pathology in a patient with a history of follicular lymphoma treated with allogeneic stem cell transplantation. The patient presented with waxing and waning bilateral limb weakness and mental status changes. MRI showed leptomeningeal, peripheral spinal cord and periventricular cerebral white matter lesions in the brain, and polymerase chain reaction on cerebrospinal fluid detected VZV DNA. The patient expired from developing atrial fibrillation that rapidly progressed to ventricular fibrillation 10 days after admission to our hospital. Autopsy revealed macrophage‐rich areas of demyelination in the spinal cord and cerebrum with relative preservation of axons associated with inclusion bodies and positive immunostaining for VZV. This case represents a rare example of VZV encephalomyelitis presenting with a predominantly demyelinating, “multiple sclerosis‐like” pathology. The clinical and histopathologic findings and relevant literature are presented and discussed.     

Remyelination in multiple sclerosis: Cellular mechanisms and novel therapeutic approaches

The myelin sheath that coats axons allows rapid propagation of electrical impulses across the nervous system. Oligodendrocytes (ODs) are myelin‐producing cells of the central nervous system (CNS) responsible for wrapping the axons of neurons. Multiple sclerosis (MS) is a demyelinating disease of the CNS identifiable by white and gray matter lesions. These lesions consist of axons that have lost their myelin through an autoimmune response to myelin and ODs. Current treatments for MS target the autoimmune aspect of the disease. However, these immunomodulators do not directly enhance the process of remyelination. The ability to remyelinate lesions can be enhanced by neural progenitor cells that can differentiate into ODs and replace lost myelin, although successful remyelination is complex and dependent on multiple factors. The restoration of lost myelin might protect the axon from degeneration and restore optimal conduction of impulses in MS patients, requiring further research on proremyelinating therapies. The combination of immunomodulators and remyelinating enhancers might be the best course of treatment for many MS patients. This Review discusses demyelination in MS, the mechanisms of remyelination, and current therapies designed to promote remyelination in MS patients. © 2014 Wiley Periodicals, Inc.     

miR-30a对实验性自身免疫性脑脊髓炎模型小鼠发病的作用

目的:探讨在体过表达miR-30a对实验性自身免疫性脑脊髓炎(EAE)模型小鼠脱髓鞘病变的作用。方法:构建含稳定表达miR-30a的shRNA慢病毒载体,以含有空载体的慢病毒为对照(LV-ctrl)。雌性C57BL/6小鼠随机分为正常对照组(normal)、对照慢病毒(LV-ctrl)组和miR-30a慢病毒(LV-miR-30a)组,2组慢病毒经尾静脉注射,注射7 d后用MOG35-55多肽免疫小鼠。Kono 5分法检测发病情况,快蓝(LFB)染色及透射电镜检测脊髓脱髓鞘程度及髓鞘结构的变化。结果:LV-ctrl组小鼠在MOG_(35-55)多肽免疫的第10天开始发病,到第21天,其Kono评分为2.57±0.79,LV-miR-30a组小鼠的Kono评分显著低于LV-ctrl组小鼠;miR-30a处理可显著提高小鼠体质量增长率,同时LFB评分也较LV-ctrl组显著增加;髓鞘超微结构显示LV-ctrl组小鼠脊髓髓鞘板层松解且稀疏,而LV-miR-30a组小鼠的髓鞘结构相对完好,髓鞘厚度显著大于LV-ctrl组。结论:过表达miR-30a可以明显减缓EAE的发病,减轻脊髓脱髓鞘程度。     

Bayesian algorithm using spatial priors for multiexponential T(2) relaxometry from multiecho spin echo MRI

Multiexponential T₂ relaxometry is a powerful research tool for detecting brain structural changes due to demyelinating diseases such as multiple sclerosis. However, because of unusually high signal‐to‐noise ratio requirement compared with other MR modalities and ill‐posedness of the underlying inverse problem, the T₂ distributions obtained with conventional approaches are frequently prone to noise effects. In this article, a novel multivoxel Bayesian algorithm using spatial prior information is proposed. This prior takes into account the expectation that volume fractions and T₂ relaxation times of tissue compartments change smoothly within coherent brain regions. Three‐dimensional multiecho spin echo MRI data were collected from five healthy volunteers at 1.5 T and myelin water fraction maps were obtained using the conventional and proposed algorithms. Compared with the conventional method, the proposed method provides myelin water fraction maps with improved depiction of brain structures and significantly lower coefficients of variance in white matter. Magn Reson Med, 2012. © 2012 Wiley Periodicals, Inc.