TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits

Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neurodegenerative process capable to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis (MS). The human endogenous retrovirus type W (HERV-W) represents an MS-specific pathogenic entity, and its envelope (ENV) protein was previously identified as a negative regulator of OPC maturation—hence, it is of relevance in the context of diminished myelin repair. We here focused on the activity of the ENV protein and investigated how it can be neutralized for improved remyelination. ENV-mediated activation of toll like receptor 4 (TLR4) increases inducible nitric oxide synthase (iNOS) expression, prompts nitrosative stress, and results in myelin-associated deficits, such as decreased levels of oligodendroglial maturation marker expression and morphological alterations. The intervention of TLR4 surface expression represents a potential means to rescue such ENV-dependent deficits. To this end, the rescue capacity of specific substances, either modulating V-ATPase activity or myeloid differentiation 2 (MD2)-mediated TLR4 glycosylation status, such as compound 20 (C20), L48H437, or folimycin, was analyzed, as these processes were demonstrated to be relevant for TLR4 surface expression. We found that pharmacological treatment can rescue the maturation arrest of oligodendroglial cells and their myelination capacity and can prevent iNOS induction in the presence of the ENV protein. In addition, downregulation of TLR4 surface expression was observed. Furthermore, mitochondrial integrity crucial for oligodendroglial cell differentiation was affected in the presence of ENV and ameliorated upon pharmacological treatment. Our study, therefore, provides novel insights into possible means to overcome myelination deficits associated with HERV-W ENV-mediated myelin deficits.

Role of Multifocal Visually Evoked Potential as a Biomarker of Demyelination, Spontaneous Remyelination, and Myelin Repair in Multiple Sclerosis

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS), characterized by inflammation, demyelination, neuro-axonal loss, and gliosis. Inflammatory demyelinating lesions are a hallmark of the disease. Spontaneous remyelination, however, is often incomplete and strategies that promote remyelination are needed. As a result, accurate and sensitive in vivo measures of remyelination are necessary. The visual pathway provides a unique opportunity for in vivo assessment of myelin damage and repair in the MS-affected brain since it is highly susceptible to damage in MS and is a very frequent site of MS lesions. The visually evoked potential (VEP), an event-related potential generated by the striate cortex in response to visual stimulation, is uniquely placed to serve as a biomarker of the myelination along the visual pathway. The multifocal VEP (mfVEP) represents a most recent addition to the array of VEP stimulations. This article provides a current view on the role of mfVEP as a biomarker of demyelination, spontaneous remyelination, and myelin repair in MS.

Clemastine improves electrophysiologic and histomorphometric changes through promoting myelin repair in a murine model of compression neuropathy

Compression neuropathies are common and debilitating conditions that result in variable functional recovery after surgical decompression. Recent drug repurposing studies have verified that clemastine promotes functional recovery through enhancement of myelin repair in demyelinating disease. We investigated the utility of clemastine as a treatment for compression neuropathy using a validated murine model of compression neuropathy encircling the compression tube around the sciatic nerve. Mice received PBS or clemastine solution for 6 weeks of compression phase. Mice taken surgical decompression received PBS or clemastine solution for 2 weeks of decompression phase. Electrodiagnostic, histomorphometric, and Western immunoblotting analyses were performed to verify the effects of clemastine. During the compression phase, mice treated with clemastine had significantly decreased latency and increased amplitude compared to untreated mice that received PBS. Histomorphometric analyses revealed that mice treated with clemastine had significantly higher proportions of myelinated axons, thicker myelin, and a lower G-ratio. The expression levels of myelin proteins, including myelin protein zero and myelin associated glycoprotein, were higher in mice treated with clemastine. However, the electrophysiologic and histomorphometric improvements were observed regardless of clemastine treatment in mice taken surgical decompression. Mice treated with clemastine during compression of the sciatic nerve demonstrated that clemastine treatment attenuated electrophysiologic and histomorphometric changes caused by compression through promoting myelin repair.

TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice

The mechanisms regulating myelin repair in the adult central nervous system (CNS) are unclear. Here, we identify DNA hydroxymethylation, catalyzed by the Ten-Eleven-Translocation (TET) enzyme TET1, as necessary for myelin repair in young adults and defective in old mice. Constitutive and inducible oligodendrocyte lineage-specific ablation of Tet1 (but not of Tet2), recapitulate this age-related decline in repair of demyelinated lesions. DNA hydroxymethylation and transcriptomic analyses identify TET1-target in adult oligodendrocytes, as genes regulating neuro-glial communication, including the solute carrier (Slc) gene family. Among them, we show that the expression levels of the Na+/K+/Cl− transporter, SLC12A2, are higher in Tet1 overexpressing cells and lower in old or Tet1 knockout. Both aged mice and Tet1 mutants also present inefficient myelin repair and axo-myelinic swellings. Zebrafish mutants for slc12a2b also display swellings of CNS myelinated axons. Our findings suggest that TET1 is required for adult myelin repair and regulation of the axon-myelin interface.

Effect of Carvacrol on Inflammatory Factors and Myelin Repair in Experimental Autoimmune Encephalomyelitis on Female Lewis Rats

Carvacrol is a phenolic monoterpene constituent of essential oils produced by plants such as Nigella sativa. This study examined the therapeutic effects of carvacrol in a model of experimental autoimmune encephalomyelitis (EAE). EAE induction was performed on female Lewis rats and, after appearance of the first clinical signs, a second EAE group received carvacrol intraperitoneally each day for 17 days. Clinical symptoms and body weight were assessed daily. All animals sacrificed and histological and gene expression analysis of the spinal cord were performed. The carvacrol treated group scored lower for disease after therapeutic administration than the control group. Gene expression analysis on the carvacrol treated group showed a decrease in TNF-α, NF-ҚB and IL-17 (pro-inflammatory) gene expression and an increase in MBP and OLIG2 remyelination markers. In the carvacrol treated group, H&E stain of spinal cord sections revealed a remarkable decrease in the amount of inflammatory cell infiltration. Immunostaining of lumbar spinal cord sections demonstrated a remarkable increase in MBP and a decrease in IL-17 secretion in the carvacrol treated group. These results demonstrate that carvacrol had a beneficial therapeutic effect and anti-inflammatory properties that significantly reduced the clinical scores and promoted myelin repair.

Canavan Disease as a Model for Gene Therapy-Mediated Myelin Repair

In recent years, the scientific and therapeutic fields for rare, genetic central nervous system (CNS) diseases such as leukodystrophies, or white matter disorders, have expanded significantly in part due to technological advancements in cellular and clinical screenings as well as remedial therapies using novel techniques such as gene therapy. However, treatments aimed at normalizing the pathological changes associated with leukodystrophies have especially been complicated due to the innate and variable effects of glial abnormalities, which can cause large-scale functional deficits in developmental myelination and thus lead to downstream neuronal impairment. Emerging research in the past two decades have depicted glial cells, particularly oligodendrocytes and astrocytes, as key, regulatory modulators in constructing and maintaining myelin function and neuronal viability. Given the significance of myelin formation in the developing brain, myelin repair in a time-dependent fashion is critical in restoring homeostatic functionality to the CNS of patients diagnosed with white matter disorders. Using Canavan Disease (CD) as a leukodystrophy model, here we review the hypothetical roles of N-acetylaspartate (NAA), one of the brain's most abundant amino acid derivatives, in Canavan disease's CNS myelinating pathology, as well as discuss the possible functions astrocytes serve in both CD and other leukodystrophies' time-sensitive disease correction. Through this analysis, we also highlight the potential remyelinating benefits of gene therapy for other leukodystrophies in which alternative CNS cell targeting for white matter disorders may be an applicable path for reparative treatment.