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Neuroprotection in a novel mouse model of multiple sclerosis.

ABSTRACT: Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes for a myelin oligodendrocyte glycoprotein-specific T cell receptor and a retinal ganglion cell restricted-Thy1 promoter-controlled cyan fluorescent protein. This model develops spontaneous or induced optic neuritis, in the absence of paralytic disease normally associated with most rodent autoimmune models of multiple sclerosis. Demyelination and neurodegeneration could be monitored longitudinally in the living animal using electrophysiology, visual sensitivity, confocal scanning laser ophthalmoscopy and optical coherence tomography all of which are relevant to human trials. This model offers many advantages, from a 3Rs, economic and scientific perspective, over classical experimental autoimmune encephalomyelitis models that are associated with substantial suffering of animals. Optic neuritis in this model led to inflammatory damage of axons in the optic nerve and subsequent loss of retinal ganglion cells in the retina. This was inhibited by the systemic administration of a sodium channel blocker (oxcarbazepine) or intraocular treatment with siRNA targeting caspase-2. These novel approaches have relevance to the future treatment of neurodegeneration of MS, which has so far evaded treatment.

SUBMITTER: Lidster K

PROVIDER: S-EPMC3817036 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Neuroprotection in a novel mouse model of multiple sclerosis.

Lidster Katie K Jackson Samuel J SJ Ahmed Zubair Z Munro Peter P Coffey Pete P Giovannoni Gavin G Baker Mark D MD Baker David D

PloS one 20131104 11

Multiple sclerosis is an immune-mediated, demyelinating and neurodegenerative disease that currently lacks any neuroprotective treatments. Innovative neuroprotective trial designs are required to hasten the translational process of drug development. An ideal target to monitor the efficacy of strategies aimed at treating multiple sclerosis is the visual system, which is the most accessible part of the human central nervous system. A novel C57BL/6 mouse line was generated that expressed transgenes ...[more]

PMID: 24223903

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Project description:BACKGROUND:Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating disease of the central nervous system (CNS), which can occur in many parts of the CNS and result in a wide range of symptoms including sensory impairment, fatigue, walking or balance problems, visual impairment, vertigo and cognitive disabilities. At present, the most commonly used MS treatments are immunomodulating agents, but they have little effect on the disability. Experimental studies show that sodium (Na(+)) accumulation leads to intracellular calcium (Ca(2+)) release, and the increased calcium levels can activate nitric oxide synthase and harmful proteases and lipases. These factors contribute to axonal injury in people with MS. If partial blockade of voltage-gated sodium channels could result in neuroprotection, this would be of benefit for preventing disability progression in these people. Neuroprotection is emerging as a potentially important strategy for preventing disability progression in people with MS. OBJECTIVES:To assess the efficacy and safety of sodium channel blockers for neuroprotection in people with MS to prevent the occurrence of disability and alleviate the burden of the disease. SEARCH METHODS:We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (27 August 2015) which, among other sources, contains references from the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library 2015, Issue (8), MEDLINE (1966 to August 2015), EMBASE (1974 to August 2015), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1981 to August 2015), Latin American and Caribbean Health Science Information Database (LILACS) (1982 to August 2015), ClinicalTrials.gov (http://clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Portal (ICTRP) search portal (http://apps.who.int/trialsearch). In addition, we searched four Chinese databases, ongoing trials registers and relevant reference lists. SELECTION CRITERIA:Randomised controlled trials (RCTs) that examined sodium channel blockers used alone or as an add-on to any approved treatments for MS. DATA COLLECTION AND ANALYSIS:Two review authors independently selected trials, assessed trial quality and extracted the data. MAIN RESULTS:Only one study evaluating lamotrigine in secondary progressive MS was eligible. One hundred and twenty people were included, 61 randomly assigned to lamotrigine treatment and 59 to placebo treatment. The average age of participants in the two groups was 51.9 years and 50.1 years, respectively. The proportion of male participants was 27.5%. The period of follow-up was 2 years. No data were found on disability progression and people who experienced relapses. No significant differences were found for serious adverse events between the two groups. Treatment with lamotrigine was associated with more rashes (20% vs 5%, P value 0.03) and transient, dose-related deterioration of mobility (66% vs 34%, P value 0.001) than placebo. Furthermore, no significant difference between the two groups was found in the magnetic resonance imaging (MRI) measurements of cerebral atrophy, Expanded Disability Status Score changes, Multiple Sclerosis Functional Composite score changes. This study was judged to be at high risk of bias. This review will be updated when the three ongoing studies we identified are completed. AUTHORS' CONCLUSIONS:The quality of evidence was judged to be very low due to the low number of available studies and included participants. There is a lack of evidence to address the review question on the efficacy of sodium channel blockers for people with MS. Assessment of the three ongoing trials might change this conclusion. Further high-quality large scale studies are needed.

Project description:Multiple sclerosis is a chronic demyelinating disorder characterized by the infiltration of auto-reactive immune cells from the periphery into the central nervous system resulting in axonal injury and neuronal cell death. Experimental autoimmune encephalomyelitis represents the best characterized animal model as common clinical, histological, and immunological features are recapitulated. A label-free mass spectrometric proteomics approach was used to detect differences in protein abundance within specific fractions of disease-affected tissues including the soluble lysate derived from the spinal cord and membrane protein-enriched peripheral blood mononuclear cells. Tissues were harvested from actively induced experimental autoimmune encephalomyelitis mice and sham-induced ("vehicle" control) counterparts at the disease peak followed by subsequent analysis by nanoflow liquid chromatography tandem mass spectrometry. Relative protein quantitation was performed using both intensity- and fragmentation-based approaches. After statistical evaluation of the data, over 500 and 250 differentially abundant proteins were identified in the spinal cord and peripheral blood mononuclear cell data sets, respectively. More than half of these observations have not previously been linked to the disease. The biological significance of all candidate disease markers has been elucidated through rigorous literature searches, pathway analysis, and validation studies. Results from comprehensive targeted mass spectrometry analyses have confirmed the differential abundance of ? 200 candidate markers (? twofold dysregulated expression) at a 70% success rate. This study is, to our knowledge, the first to examine the cell-surface proteome of peripheral blood mononuclear cells in experimental autoimmune encephalomyelitis. These data provide a unique mechanistic insight into the dynamics of peripheral immune cell infiltration into CNS-privileged sites at a molecular level and has identified several candidate markers, which represent promising targets for future multiple sclerosis therapies. The mass spectrometry proteomics data associated with this manuscript have been deposited to the ProteomeXchange Consortium with the data set identifier PXD000255.

Project description:INTRODUCTION:Progressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%-70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing-remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol-treated compared to placebo-treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes. METHODS:Sixty-two estriol- and forty-nine placebo-treated RRMS patients underwent clinical evaluations and brain MRI. Voxel-based morphometry (VBM) was used to evaluate voxelwise GM sparing from high-resolution T1-weighted scans. RESULTS:A region of treatment-induced sparing (TIS) was defined as the areas where GM was spared in estriol- as compared to placebo-treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability-specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol-treated subjects that was associated with better performance on the PASAT. CONCLUSIONS:Discovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability-specific biomarker for clinical trials of candidate neuroprotective treatments in MS.

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Neuroprotection in a novel mouse model of multiple sclerosis.

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Neuroprotection in a novel mouse model of multiple sclerosis.

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