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ABSTRACT: Introduction: Vitamin D has attracted a lot of attention in relation to multiple sclerosis (MS) and many other disorders; however, the evidence for a major role(s) for vitamin D in MS is compelling and multifactorial involving results from epidemiology, immunology, genetics, biochemistry and translational medicine. Areas covered: Multiple studies that illustrate that insufficient levels of vitamin D not only contribute to the risk of getting MS but may also worsen disease progression for MS patients are discussed. Genetic evidence also implicates vitamin D as being important in MS since individuals are at greater risk of getting MS if they harbor a mutation in a gene responsible for vitamin D synthesis (25-hydroxylase). Other modifiers of MS disease appear to interact with the vitamin D receptor. The Epstein-Barr virus (EBV) is a risk factor for MS and may in part worsen disease through the interactions between one of its gene products (EBNA-3) and the vitamin D receptor to attenuate vitamin D-regulated genes. Retrospective studies have shown that higher vitamin D levels are associated with a significant improvement of clinical and magnetic resonance imaging outcomes. Increasing clinical observations are also indicating adverse effects of low vitamin D in MS. Expert opinion: Mounting evidence from epidemiology, genetic, retrospective clinical studies and emerging basic science studies support a strong rationale for how vitamin D could be an important modifier of MS disease. Well-designed clinical trials are now ongoing and will provide further insight on how vitamin D supplementation may impact MS.
Expert Opinion on Medical Diagnostics 02/2013;
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ABSTRACT: Patients with therapy-induced neutralizing antibodies (NAbs) to interferon-beta (IFN-β) have reduced responses to IFN-β treatment, resulting in higher relapse rates, increased magnetic resonance imaging activity, and a higher risk of disease progression. A functional assay was employed for both screening and titering of IFN-β NAbs utilizing a human cell line transfected with a luciferase reporter gene responsive to IFN-β. This assay demonstrated 100% sensitivity and specificity compared with the traditional cytopathic effect (CPE) assay and normal donor specimens. Additionally, 183 patients with multiple sclerosis (MS) undergoing therapy with IFN-β were tested in the reporter gene assay. Percent positivity for NAbs to the IFN-β was as follows: Avonex (1α) 26.5%, Rebif (1α) 34.1%, and Betaseron (1β) 31.8%. The IFN-β reporter gene assay showed excellent correlation with the well-established CPE assay offering clear advantages. The 50% false-positivity rate typically seen in enzyme-linked immunosorbent assays could be eliminated by using a functional assay for both screening and titering. Results can be reported within 20 h, and the cell line is cryopreserved, eliminating the need to maintain live viral and cell cultures. The use of this functional assay should be a valuable tool for detecting and monitoring the presence of NAbs in IFN-β-treated patients with MS.
Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 11/2012; · 1.63 Impact Factor
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ABSTRACT: Introduction: Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that leads to axonal dysfunction and neuronal loss and often presents optic neuritis (ON). Decreased thickness of the retinal nerve fiber layer (RNFL) is a classic finding on ophthalmoscopic examination of patients with MS and especially noted in those patients with a history of ON. The thickness of the RNFL can be measured by a non-invasive technique, optical coherence tomography (OCT). Areas covered: This review will cover the history and development of the OCT technology and the advantages of a potential clinical application as a biomarker for axonal loss in MS. Expert opinion: The use of OCT to quantify axonal loss in the RNFL is a promising tool to evaluate disease progression in MS and ON patients. OCT measurements may also correlate with MRI measured brain atrophy and could provide an easily quantified and highly reproducible method in clinical trials to monitor the efficacy of both immune- and neuroprotective therapies. Potential correlations between OCT with other biomarkers that include low contrast vision, visual evoked potentials, color vision and diffusion tensor imaging of the brain and advanced imaging of the optic nerve are promising new frontiers of research.
Expert Opinion on Medical Diagnostics 11/2012; 6(6):593-604.
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John W Rose
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ABSTRACT: Complex combinatorial mechanisms of innate and adaptive immunity and antigen presentation collaborate to effect monoclonal antibody therapy in multiple sclerosis (Perry et al., this issue).
Science translational medicine 08/2012; 4(145):145fs25. · 7.80 Impact Factor
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ABSTRACT: Monoclonal antibodies (MAbs) may have great potential as therapies for autoimmune diseases. Their development as treatments
for multiple sclerosis (MS) is promising. Partially effective immunomodulatory therapies have been helpful for many MS patients;
however, for patients failing these immunomodulatory treatments, MAbs are an important new treatment option. Currently, MAbs
are approved by the US Food and Drug Administration for treatment of many conditions, including autoimmune diseases. Four
MAbs that have been investigated as potential treatments for MS are reviewed in this article. Of these MAbs, natalizumab is
approved for treatment of MS. The other three MAbs (alemtuzumab, rituximab, and daclizumab) are all promising therapies in
development for treatment of MS. Adverse effects are relatively mild for these MAbs; however, care in administration and management
of these agents is emphasized. Overall, these MAb therapies have great promise in the treatment of MS.
Current Neurology and Neuroscience Reports 04/2012; 8(5):419-426. · 3.45 Impact Factor
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ABSTRACT: We examined cytokines and other inflammatory markers in serum samples from 833 patients with multiple sclerosis and 117 healthy control subjects. A multiplexed immunoassay was used to assess the concentrations of 13 cytokines/inflammatory markers: interferon (IFN)-γ; interleukins (ILs)-1β, 2, 4, 5, 6, 8, 10, 12, and 13; tumor necrosis factor (TNF)-α; IL-2 receptor; and soluble CD40 ligand. Significant increases between patients and control subjects were found for IFN-γ (mean, 7.5 vs 0.4 pg/mL; P = .0002), IL-2 (mean 5.7 vs 1.0 pg/mL; P =.0002), IL-1β (mean, 23.0 vs 11.3 pg/mL; P ≤ .0001), TNF-α (mean, 4.1 vs 1.2 pg/mL; P = .01), IL-4 (mean, 1.4 vs 0.1 pg/mL; P ≤ .0001), IL-10 (mean, 16.8 vs 7.5 pg/mL; P = .03), and IL-13 (mean, 4.5 vs 0.8 pg/mL; P ≤ .0001). Profiling cytokines in multiple sclerosis may help to identify mechanisms involved in the pathogenesis of the disease, aid in monitoring the disease course and in evaluating responses to specific therapies, and, potentially, lead to new therapies directed at cytokines or their receptors.
American Journal of Clinical Pathology 11/2011; 136(5):696-704. · 2.60 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a debilitating disease with an assumed autoimmune etiology which may lead to elevated oxidative stress, vascular dysfunction, and subsequent predisposition to cardiovascular disease. Therefore, the primary aim of this study was to evaluate vascular function and the potential role of oxidative stress in patients diagnosed with MS compared to healthy controls (C). Fourteen patients with relapsing-remitting MS (47 ± 3 years) and 13 age- and activity-matched controls (44 ± 5 years) underwent brachial artery flow-mediated dilation (FMD) and reactive hyperemia testing using ultrasound Doppler. Venous blood was analyzed for C-reactive protein (CRP), lipid hydroperoxides (LH), the ferric reducing ability of plasma (FRAP), superoxide dismutase (SOD), and catalase activity. CRP [1.8 ± 0.5 mg/L (MS), 1.0 ± 0.5 mg/L (C)] and LH [1.2 ± 0.2 μmol/L (MS), 1.1 ± 0.1 μmol/L (C)] were not different between MS patients and controls. FMD [8.0 ± 1.2% (MS) and 9.2 ± 1.6% (C)] and reactive hyperemia [380 ± 61 mL (MS) and 402 ± 69 mL (C)] were also not different between groups. Vascular function, as assessed by both FMD and reactive hyperemia, was not impaired in patients with MS compared to controls. Further, there was no evidence of elevated systemic inflammation or oxidative stress in these patients, who were currently all in remission. These findings suggest that impaired vascular function, elevated inflammation and oxidative stress are not an obligatory accompaniment to MS.
Journal of Neurology 05/2011; 258(11):2036-42. · 3.47 Impact Factor
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ABSTRACT: Introduction: The search for meaningful biomarkers for multiple sclerosis (MS) has intensified in the past 5 years. Substantial progress is continuing in this multifaceted field. Recent advances offer important potential for new clinical tools to assist in diagnosis, detection of disease-associated conditions or cofactors, assessment of treatment efficacy and determination of disease progression. There are several new therapies for MS that are in development. Biomarkers that could identify and monitor the effectiveness of therapies would be of great advantage as the range of therapies for MS is rapidly expanding. Areas covered: In this review, recent advances in biomarkers identified by clinical measures, genetic markers, serologic markers, cerebrospinal fluid markers, MRI measures and biomarkers associated with therapies are highlighted. Areas of recent progress are presented that may lead to useful biomarkers that could emerge in clinical practice for the treatment of MS patients. Expert opinion: The discovery of new biomarkers for MS not only brings with it the opportunity to have a greater understanding of the pathogenesis of the disease, but also holds the promise for future diagnostic tools and better treatment strategies for MS.
Expert Opinion on Medical Diagnostics 05/2011; 5(3):213-26.
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ABSTRACT: To determine the ability of the principal diffusion tensor imaging (DTI) indices to predict the underlying histopathology evaluated with immunofluorescent assay (IFA).
Conventional T2 and 3D multishot-diffusion weighted echoplanar imaging (3D ms-DWEPI) was performed on a fixed, ex vivo human cervical spinal cord (CSC) from a patient with a history of multiple sclerosis (MS). In all, 170 regions of interest (ROIs) were selected within the white matter and categorized as a high intensity lesion (HIL), low intensity lesion (LIL), and normal-appearing white matter (NAWM). The longitudinal diffusivity (λl), radial diffusivity (λr), and fractional anisotropy (FA) were obtained from each ROI. The underlying histopathology was then evaluated using immunofluorescent assay with antibodies directed to myelin and neurofilament staining.
The mean values for λl and λr were significantly elevated within HIL relative to NAWM and LIL. IFA analysis of HIL demonstrated significant demyelination, without significant if any axon loss. The FA values were significantly reduced in HIL and LILs. FA values were also reduced in lesions with increased λl and λr values relative to normal.
Aberrant λl, λr, and FA relative to normal values are strong indicators of demyelination. DTI indices are not specific for axon loss. IFA analysis is a reliable method to demonstrate myelin and axon pathology within the ex vivo setting.
Journal of Magnetic Resonance Imaging 03/2011; 33(3):557-64. · 2.70 Impact Factor
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ABSTRACT: We previously found that cyclooxygenase 2 (COX-2) was expressed in dying oligodendrocytes at the onset of demyelination in the Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model of multiple sclerosis (MS) (Carlson et al. J.Neuroimmunology 2006, 149:40). This suggests that COX-2 may contribute to death of oligodendrocytes.
The goal of this study was to examine whether COX-2 contributes to excitotoxic death of oligodendrocytes and potentially contributes to demyelination.
The potential link between COX-2 and oligodendrocyte death was approached using histopathology of MS lesions to examine whether COX-2 was expressed in dying oligodendrocytes. COX-2 inhibitors were examined for their ability to limit demyelination in the TMEV-IDD model of MS and to limit excitotoxic death of oligodendrocytes in vitro. Genetic manipulation of COX-2 expression was used to determine whether COX-2 contributes to excitotoxic death of oligodendrocytes. A transgenic mouse line was generated that overexpressed COX-2 in oligodendrocytes. Oligodendrocyte cultures derived from these transgenic mice were used to examine whether increased expression of COX-2 enhanced the vulnerability of oligodendrocytes to excitotoxic death. Oligodendrocytes derived from COX-2 knockout mice were evaluated to determine if decreased COX-2 expression promotes a greater resistance to excitotoxic death.
COX-2 was expressed in dying oligodendrocytes in MS lesions. COX-2 inhibitors limited demyelination in the TMEV-IDD model of MS and protected oligodendrocytes against excitotoxic death in vitro. COX-2 expression was increased in wild-type oligodendrocytes following treatment with Kainic acid (KA). Overexpression of COX-2 in oligodendrocytes increased the sensitivity of oligodendrocytes to KA-induced excitotoxic death eight-fold compared to wild-type. Conversely, oligodendrocytes prepared from COX-2 knockout mice showed a significant decrease in sensitivity to KA induced death.
COX-2 expression was associated with dying oligodendrocytes in MS lesions and appeared to increase excitotoxic death of oligodendrocytes in culture. An understanding of how COX-2 expression influences oligodendrocyte death leading to demyelination may have important ramifications for future treatments for MS.
Journal of Neuroinflammation 04/2010; 7:25. · 3.83 Impact Factor
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Daniel Wynn,
Michael Kaufman,
Xavier Montalban,
Timothy Vollmer,
Jack Simon,
Jacob Elkins,
Gilmore O'Neill,
Lauri Neyer,
James Sheridan,
Chungchi Wang,
Alice Fong, John W Rose
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ABSTRACT: Daclizumab, a humanised monoclonal antibody, reduced multiple sclerosis disease activity in previous non-randomised studies. We aimed to assess whether daclizumab reduces disease activity in patients with active relapsing multiple sclerosis who are receiving interferon beta treatment.
We did a phase 2, randomised, double-blind, placebo-controlled study at 51 centres in the USA, Canada, Germany, Italy, and Spain. Patients with active relapsing multiple sclerosis who were taking interferon beta were randomly assigned to receive add-on subcutaneous daclizumab 2 mg/kg every 2 weeks (interferon beta and high-dose daclizumab group), daclizumab 1 mg/kg every 4 weeks (interferon beta and low-dose daclizumab group), or interferon beta and placebo for 24 weeks. The randomisation scheme was generated by Facet Biotech. All patients and assessors were masked to treatment with the exception of Facet Biotech bioanalysts who prepared data for the data safety monitoring board or generated pharmacokinetic or pharmacodynamic data, a drug accountability auditor, and the site pharmacist. The primary endpoint was total number of new or enlarged gadolinium contrast-enhancing lesions measured on brain MRI scans every 4 weeks between weeks 8 and 24. Effects of daclizumab on prespecified subsets of lymphocytes and quantitative T-cell proliferative response were assessed in an exploratory pharmacodynamic substudy. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00109161.
From May, 2005, to March, 2006, 288 patients were assessed for eligibility, and 230 were randomly assigned to receive interferon beta and high-dose daclizumab (n=75), interferon beta and low-dose daclizumab (n=78), or interferon beta and placebo (n=77). The adjusted mean number of new or enlarged gadolinium contrast-enhancing lesions was 4.75 in the interferon beta and placebo group compared with 1.32 in the interferon beta and high-dose daclizumab group (difference 72%, 95% CI 34% to 88%; p=0.004) and 3.58 in the interferon beta and low-dose daclizumab group (25%, -76% to 68%; p=0.51). In the pharmacodynamic substudy, daclizumab was not associated with significant changes in absolute numbers of T cells, B cells, or natural killer cells, or T-cell proliferative response compared with interferon beta alone. The number of CD56(bright) natural killer cells was seven to eight times higher in both daclizumab groups than in the interferon beta and placebo group (interferon beta and low-dose daclizumab group p=0.002; interferon beta and high-dose daclizumab group p<0.0001). Common adverse events were equally distributed across groups.
Add-on daclizumab treatment reduced the number of new or enlarged gadolinium contrast-enhancing lesions compared with interferon beta alone and might reduce multiple sclerosis disease activity to a greater extent than interferon beta alone.
Facet Biotech and Biogen Idec.
The Lancet Neurology 02/2010; 9(4):381-90. · 23.46 Impact Factor
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Johannes Brettschneider,
Troy D Jaskowski,
Hayrettin Tumani,
Sana Abdul,
Dee Husebye,
Haniah Seraj,
Harry R Hill,
Ella Fire,
Larissa Spector,
Jennifer Yarden,
Nir Dotan, John W Rose
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ABSTRACT: The serum level of IgM antibodies against Glc(alpha1,4)Glc(alpha) (GAGA4) is higher in relapsing remitting multiple sclerosis (RRMS) compared to other neurological disease (OND) patients and healthy controls (HC). Detecting the level of anti-GAGA4 antibody by enzyme immunoassay and total IgM, we confirmed that anti-GAGA4 IgM can differentiate RRMS from OND patients and HC. Moreover, secondary progressive MS (SPMS) and RRMS patients have similar levels of anti-GAGA4 demonstrating the biomarker's presence throughout the disease. Interestingly, the anti-GAGA4 assay may also differentiate between primary progressive MS (PPMS) and RRMS/SPMS patients, since nearly all PPMS patients were negative for the assay.
Journal of neuroimmunology 10/2009; 217(1-2):95-101. · 2.84 Impact Factor
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ABSTRACT: We performed a retrospective review of side effects and clinical outcomes in relapsing-remitting (RR) multiple sclerosis (MS) patients receiving long-term treatment with daclizumab. Twelve patients with RR MS were initially treated with daclizumab at 1 mg/kg IV, again 14 days later and then monthly treatments (average duration 42.1 months). Daclizumab dose (0.85 mg/kg to 1.5 mg/kg) was adjusted based on clinical response. Daclizumab was generally well tolerated. There was a significant reduction in relapse rate and improvement in Expanded Disability Status Scores (EDSSs) (p < 0.0001). Long-term treatment with daclizumab in RR MS patients has apparent benefit that will require formal confirmation.
Therapeutic Advances in Neurological Disorders 09/2009; 2(5):291-7.
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John W Rose
Neurology 08/2009; 73(8):578-9. · 8.31 Impact Factor
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ABSTRACT: Monoclonal antibodies (MAbs) may have great potential as therapies for autoimmune diseases. Their development as treatments for multiple sclerosis (MS) is promising. Partially effective immunomodulatory therapies have been helpful for many MS patients; however, for patients failing these immunomodulatory treatments, MAbs are an important new treatment option. Currently, MAbs are approved by the US Food and Drug Administration for treatment of many conditions, including autoimmune diseases. This article reviews four MAbs that have been investigated as potential treatments for MS. Of these MAbs, natalizumab is approved for treatment of MS. The other three MAbs (alemtuzumab, rituximab, and daclizumab) are all promising therapies in development for treatment of MS. Adverse effects are relatively mild for these MAbs; however, care in administration and management of these agents is emphasized. Overall, these MAb therapies have great promise in the treatment of MS.
Current Treatment Options in Neurology 06/2009; 11(3):211-20. · 1.29 Impact Factor
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ABSTRACT: Immunoglobulin G (IgG) antibodies reactive with intracellular neuronal proteins have been described in paraneoplastic and other autoimmune disorders. Because neurons have been thought impermeable to immunoglobulins, however, such antibodies have been considered unable to enter neurons and bind to their specific antigens during life. Cerebellar Purkinje cells - an important target in paraneoplastic and other autoimmune diseases - have been shown in experimental animals to incorporate a number of molecules from cerebrospinal fluid. IgG has also been detected in Purkinje cells studied post mortem. Despite the possible significance of these findings for human disease, immunoglobulin uptake by Purkinje cells has not been demonstrated in living tissue or studied systematically.
To assess Purkinje cell uptake of immunoglobulins, organotypic cultures of rat cerebellum incubated with rat IgGs, human IgG, fluorescein-conjugated IgG, and rat IgM were studied by confocal microscopy in real time and following fixation. An IgG-daunorubicin immunotoxin was used to determine whether conjugation of pharmacological agents to IgG could be used to achieve Purkinje cell-specific drug delivery.
IgG uptake was detected in Purkinje cell processes after 4 hours of incubation and in Purkinje cell cytoplasm and nuclei by 24-48 hours. Uptake could be followed in real time using IgG-fluorochrome conjugates. Purkinje cells also incorporated IgM. Intracellular immunoglobulin did not affect Purkinje cell viability, and Purkinje cells cleared intracellular IgG or IgM within 24-48 hours after transfer to media lacking immunoglobulins. The IgG-daunomycin immunotoxin was also rapidly incorporated into Purkinje cells and caused extensive, cell-specific death within 8 hours. Purkinje cell death was not produced by unconjugated daunorubicin or control IgG.
Purkinje cells in rat organotypic cultures incorporate and clear host (rat) and non-host (human or donkey) IgG or IgM, independent of the immunoglobulin's reactivity with Purkinje cell antigens. This property permits real-time study of immunoglobulin-Purkinje cell interaction using fluorochrome IgG conjugates, and can allow Purkinje cell-specific delivery of IgG-conjugated pharmacological agents. Antibodies to intracellular Purkinje cell proteins could potentially be incorporated intracellularly to produce cell injury. Antibodies used therapeutically, including immunotoxins, may also be taken up and cause Purkinje cell injury, even if they do not recognize Purkinje cell antigens.
Journal of Neuroinflammation 01/2009; 6:31. · 3.83 Impact Factor
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ABSTRACT: Monoclonal antibodies (MAbs) may have great potential as therapies for autoimmune diseases. Their development as treatments for multiple sclerosis (MS) is promising. Partially effective immunomodulatory therapies have been helpful for many MS patients; however, for patients failing these immunomodulatory treatments, MAbs are an important new treatment option. Currently, MAbs are approved by the US Food and Drug Administration for treatment of many conditions, including autoimmune diseases. Four MAbs that have been investigated as potential treatments for MS are reviewed in this article. Of these MAbs, natalizumab is approved for treatment of MS. The other three MAbs (alemtuzumab, rituximab, and daclizumab) are all promising therapies in development for treatment of MS. Adverse effects are relatively mild for these MAbs; however, care in administration and management of these agents is emphasized. Overall, these MAb therapies have great promise in the treatment of MS.
Current Neurology and Neuroscience Reports 10/2008; 8(5):419-26. · 3.45 Impact Factor
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ABSTRACT: Optic neuritis (ON) is a demyelinating inflammation of the optic nerve that may occur as an isolated disease or related to multiple sclerosis (MS). There is little evidence of whether the immunohistochemistry of ON resembles that of typical cerebral MS lesions.
Pathologic optic nerves were obtained from a patient who died of causes unrelated to ON after clinical recovery from clinically isolated ON. Normal control optic nerves were obtained from an eye bank. Normal and pathologic tissues were probed with antibodies to pathologic proteins including myelin basic protein (MBP) fragment, the inducible form of nitric oxide synthase (iNOS), macrophage markers CD14 and CD64, nitrotyrosine, and cyclooxygenase (COX-2). We also examined MBP, the oligodendrocyte marker cyclic nucleotide phosphodiesterase (CNPase), and glial fibrillary acidic protein.
In the affected pathologic nerve, iNOS-positive macrophages/microglia, iNOS-positive astrocytes, COX-2, and nitrotyrosine were observed. iNOS and COX-2 were occasionally observed in the unaffected nerve. Decreased expression of MBP and CNPase was seen in the pathologic optic nerves, along with evidence of gliosis and ongoing myelin degradation indicated by the presence of MBP fragment.
The immunohistochemistry of clinically isolated optic neuritis, as judged by this single case, resembles that of cerebral lesions of MS in showing abnormally high levels of iNOS and nitrotyrosine as well as other mediators of immune damage.
Journal of Neuro-Ophthalmology 07/2006; 26(2):87-94. · 1.45 Impact Factor
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ABSTRACT: The objective of this study was examine whether the inducible isoform of the enzyme cyclooxygenase (COX-2) was expressed in dying oligodendrocytes in the Theiler's murine encephalomyelitis virus (TMEV) induced demyelinating disease (TMEV-IDD), an experimental animal model for multiple sclerosis (MS). COX-2 is an enzyme that is tightly coupled to neuronal excitotoxic death. Since neuronal expression of COX-2 contributes to the susceptibility of neurons to excitotoxic death, we asked whether COX-2 was expressed in oligodendrocytes in MS plaques and in lesions during TMEV-IDD. COX-2 was expressed in oligodendrocytes in chronic active lesions from two MS patients. Similar pathology was present in TMEV-IDD spinal cord lesions. COX-2 was expressed in oligodendrocytes four weeks after infection with TMEV coincident with the onset of demyelination. A marker for apoptotic death, activated caspase 3, was present in a subset of oligodendrocytes that expressed COX-2. Oligodendrocyte expression of COX-2 in TMEV-IDD and MS lesions is consistent with a pathological role for this enzyme in demyelination. The presence of the cell death marker (activated caspase 3) with COX-2 in oligodendrocytes is direct evidence linking COX-2 with cell death of oligodendrocytes in these demyelinating diseases.
Journal of Neuroimmunology 06/2006; 174(1-2):21-31. · 2.96 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is an immune-mediated disease, with inflammation and neurodegeneration contributing to neuronal demyelination and axonal injury. Current therapies for MS are directed toward modulation of the immune response; however, there is increasing evidence that oxidative stress is an important component in the pathogenesis of MS. The inflammatory environment in demyelinating lesions is conducive to the generation of reactive oxygen species. When these species are generated in MS and animal models of MS, products such as peroxynitrite and superoxide are formed that are highly toxic to cells. There are several examples of potential beneficial effects from various antioxidants in animal models of MS, but the efficacy may vary between different agents and, in some instances, may yield deleterious effects. Despite these promising results in animal models, there is limited and conflicting evidence of potential therapeutic effects of antioxidants such as vitamins C and E in treating MS. However, clinical trials in MS patients with more potent antioxidants, identified in animal studies, have been initiated.
CNS Drugs 02/2006; 20(6):433-41. · 4.80 Impact Factor
