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Nitric Oxide

  1. Selective Inhibition of Human Glial Inducible Nitric Oxide synthase by Interferon-beta
    Ann Neurol 43: 384-7 (1998)

  2. Pretreatment of Astrocytes with Interferon-alpha ß prevents Neuronal Mitochondrial Respiratory Chain Damage
    J NeuroChem 1998 Jan;70(1):432-434

  3. Nitric Oxide metabolites and InterLeukin-6 in CerebroSpinal Fluid from Multiple Sclerosis
    Eur J Neurol 2002 Jul;9(4):413-8

  4. Role of Nitric Oxide in inflammation-mediated NeuroDegeneration
    Ann N Y Acad Sci 2002 May;962:318-31

  5. CSF Nitric Oxide metabolites are associated with activity and progression of Multiple Sclerosis
    Neurology 2004 Oct 26;63(8):1439-45

    1. Selective Inhibition of Human Glial Inducible Nitric Oxide synthase by Interferon-beta
      Ann Neurol 43: 384-7 (1998)

    2. Pretreatment of Astrocytes with Interferon-alpha ß prevents Neuronal Mitochondrial Respiratory Chain Damage
      J NeuroChem 1998 Jan;70(1):432-434

    3. Nitric Oxide metabolites and InterLeukin-6 in CerebroSpinal Fluid from Multiple Sclerosis
      Eur J Neurol 2002 Jul;9(4):413-8

    4. Role of Nitric Oxide in inflammation-mediated NeuroDegeneration
      Ann N Y Acad Sci 2002 May;962:318-31

    5. CSF Nitric Oxide metabolites are associated with activity and progression of Multiple Sclerosis
      Neurology 2004 Oct 26;63(8):1439-45

    1. Nitric Oxide: a regulator of Mast Cell activation and Mast Cell-mediated inflammation
      Clin Exp Immunol 2002 Jul;129(1):4-10

    2. Expression of inducible Nitric Oxide Synthase and NitroTyrosine in Multiple Sclerosis lesions
      Am J Pathol 2001 Jun;158(6):2057-66

    3. Serum inflammatory markers and clinical/MRI markers of disease progression in Multiple Sclerosis
      J Neurol 2001 Jun;248(6):487-95

    4. Electrically active Axons degenerate when exposed to Nitric Oxide
      Ann Neurol 2001 Apr;49(4):470-6

    5. LPS/IFN-gamma cytotoxicity in Oligodendroglial Cells: role of Nitric Oxide and protection by the anti-inflammatory Cytokine IL-10
      Eur J NeuroSci 2001 Feb;13(3):493-502

    6. Regulation by IFN-beta of Inducible Nitric Oxide Synthase and InterLeukin-12/p40 in Murine Macrophages Cultured in the Presence of Chlamydia Pneumoniae Antigens
      J Interferon Cytokine Res 2001 Mar;21(3):137-46

    7. Female sex steroids: effects upon Microglial cell activation
      J NeuroImmunol 2000 Nov 1;111(1-2):77-85

    8. Expression of inducible Nitric Oxide synthase and NitroTyrosine in Multiple Sclerosis lesions
      Am J Pathol 2001 Jun;158(6):2057-66

    9. Nitric Oxide Blocks Axonal Conduction
      Brain 1997 Dec;120( Pt 12):2149-2157

    10. Interferon-ß-1-b (IFN-ß) decreases induced Nitric Oxide (NO) production by a human Astrocytoma cell line
      J NeuroImmunol 1998 Mar 1;82(2):133-9





    #1

    Nitric Oxide Synthase
    Inhibited By Interferon-ß

    Hua LL; Liu JS; Brosnan CF; Lee SC
    Ann Neurol 43: 384-7 (1998)
    Albert Einstein College of Medicine, Dept of Pathology (Neuropathology), Bronx, NY 10461, USA
    UI# 98165381
    Abstract

    Nitric Oxide generated from the Inducible Nitric Oxide Synthase (INOS) has been implicated in the PathoGenesis of Multiple Sclerosis.

    Because significant species and cell-specific differences exist in the expression of INOS, we used primary human Glial cell cultures to screen for an inhibitor of INOS expression.

    Remarkably, among numerous soluble factors tested, Interferon-beta (IFN-ß) alone showed a selective and potent inhibition of InterLeukin-ß/Interferon-gamma (IL-ß/IFN-γ) induced INOS expression in Astrocytes.

    Inhibition of INOS may provide a mechanism by which IFN-ß can ameliorate Inflammation and CytoToxicity in the Central Nervous System of patients with MS.



    #2

    Pretreatment Of Astrocytes With Interferon-alpha ß Prevents Neuronal Mitochondrial Respiratory Chain Damage

    Stewart VC, Land JM, Clark JB, Heales SJ
    J NeuroChem 1998 Jan;70(1):432-434
    Institute of Neurology, Dept of NeuroChemistry, London, England
    UI# 98082855
    Abstract

    Excessive Nitric Oxide/Peroxynitrite generation has been implicated in the PathoGenesis of Multiple Sclerosis, and the demonstration of increased Astrocytic Nitric Oxide Synthase activity in the postmortem Brain of Multiple Slerosis patients supports this hypothesis.

    Interferon-ß is used for the treatment of Multiple Sclerosis, but currently little is known regarding its mode of action.

    Exposure of Astrocytes in culture to Interferon-γ plus LipoPolySaccharide results in stimulation of Nitric Oxide release.

    Using a co-culture system, we have been able to use Astrocytes as a source of Nitric Oxide/Peroxynitrite in an attempt to "model" the effects of raised Cytokine levels observed in Multiple Sclerosis and to monitor the effect on Neurons.

    Our results indicate that stimulation of Astrocytic Nitric Oxide Synthase activity causes significant damage to the Mitochondrial activities of complexes II/III and IV of neighboring Neurons.

    This damage was prevented by a Nitric Oxide Synthase inhibitor, suggesting that the damage was Nitric Oxide-mediated. Furthermore, Interferon-alpha/ß also prevented this damage.

    In view of these results, we suggest that a possible mechanism of action of IFN-ß in the treatment of Multiple Sclerosis is that it prevents Astrocytic Nitric Oxide production, thereby limiting damage to neighboring cells, such as Neurons.



    #3

    Nitric Oxide Metabolites And InterLeukin-6 In CerebroSpinal Fluid From Multiple Sclerosis

    Miljkovic Dj, Drulovic J, Trajkovic V, Mesaros S, Dujmovic I, Maksimovic D, Samardzic T, Stojsavljevic N, Levic Z, Mostarica Stojkovic M
    Eur J Neurol 2002 Jul;9(4):413-8
    Institute for Biological Research Sinisa Stankovic, Belgrade, Yugoslavia
    PMID# 12099927; UI# 22095208
    Abstract

    InterLeukin-6 (IL-6) and Nitric Oxide (NO) are implicated in the pathology of Multiple Sclerosis (MS). We have investigated the levels of these mediators in the CerebroSpinal Fluid (CSF) from 50 patients with MS and 23 control subjects.

    Mean CSF IL-6 level was higher in the total MS group in comparison with controls, but not significantly, whilst the difference between patients with stable MS and controls reached the level of statistical significance.

    Mean CSF Nitrite/Nitrate level was significantly higher in the total MS group compared with the control group, as well as in active MS patients versus controls.

    There was significant difference neither in the mean CSF IL-6 nor in Nitrite/Nitrate levels between active and stable MS patients.

    Interestingly, we observed a significant negative correlation between IL-6 and Nitrite/Nitrate levels in the CSF in the total MS group.

    Such a trend existed in both subgroups with active and stable MS, but without reaching the level of statistical significance.

    Our data further support the involvement of IL-6 and NO in ongoing pathological processes in MS, suggesting their potential interplay within the Central Nervous System in this disease.



    #4

    Role Of Nitric Oxide In Inflammation-Mediated NeuroDegeneration

    Liu B, Gao HM, Wang JY, Jeohn GH, Cooper CL, Hong JS
    Ann N Y Acad Sci 2002 May;962:318-31
    National Institutes of Health, National Institute of Environmental Health Sciences, NeuropPharmacology Section, Laboratory of Pharmacology and Chemistry, Research Triangle Park, North Carolina 27710, USA
    PMID# 12076984; UI# 22071475
    Abstract

    Increasing evidence has suggested that inflammation in the Brain is closely associated with the pathogenesis of several Degenerative Neurologic Disorders, including Parkinson's Disease, Alzheimer's Diseases, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and AIDS Dementia.

    The hallmark of Brain inflammation is the activation of Glial Cells, especially that of Microglia that produce a variety of ProInflammatory and NeuroToxic factors, including Cytokines, Fatty Acid Metabolites, Free Radicals - such as Nitric Oxide (NO) and SuperOxide.

    Excessive production of NO, as a consequence of Nitric Oxide Synthase induction in activated Glia, has been attributed to participate in NeuroDegeneration.

    Using primary mixed Neuron-Glia cultures and Glia-enriched cultures prepared from embryonic rodent Brain tissues, we have systemically studied the relationship between the production of NO and NeuroDegeneration in response to stimulation by the inflammagen LipopolySaccharide.

      This review summarizes our recent findings on the kinetics of NO generation:
      1. The relative contribution of Microglia and Astrocytes to NO accumulation
      2. The relationship between NO production and NeuroDegeneration
      3. Points of intervention along the pathways associated with NO generation to achieve NeuroProtection

    We also describe our results relating to the effect of several Opioid-related agents on Microglial activation and NeuroProtection.

    Among these agents, the Opioid Receptor Antagonist Naloxone, especially its NonOpioid Enantiomer +-Naloxone, promises to be of potential therapeutic value for the treatment of Inflammation-Related Diseases.



    #5

    CSF Nitric Oxide Metabolites Are Associated With Activity And Progression Of Multiple Sclerosis

    Rejdak K, Eikelenboom MJ, Petzold A, Thompson EJ, Stelmasiak Z, Lazeron RH, Barkhof F, Polman CH, Uitdehaag BM, Giovannoni G
    Neurology 2004 Oct 26;63(8):1439-45
    Institute of Neurology, Department of NeuroInflammation, London, UK
    PMID# 15505162
    Abstract

    Objective
    To investigate the relationship of CSF and the Serum Nitric Oxide metabolites Nitrite and Nitrate (NOx) to disease activity and progression in patients with Multiple Sclerosis (MS).

    Methods
    The study was divided into cross-sectional and follow-up. In the cross-sectional study, 20 patients with Relapsing/Remitting (RR), 21 with Secondary/Progressive (SP), and 10 with Primary/Progressive (PP) MS and 14 control subjects were included.

    Patients were assessed on clinical (Expanded Disability Status Scale [EDSS], Ambulation Index [AI], 9-Hole Peg Test [9-HPT]) and MRI measurements.

    In the follow-up study, 34 MS patients from the cross-sectional study agreed to be assessed again after an average of 3.0 +/- 0.5 years. NOx was measured using a vanadium-based assay.

    Results
    In the cross-sectional study, CSF NOx was raised in patients with RR-MS (p = 0.001) and PP-MS (p = 0.02) vs controls.

    Higher CSF NOx levels were found in patients with mild disability (AI < or = 6.0; EDSS < or = 4.0; Multiple Sclerosis Severity Score [MSSS] < or = 4.8) vs patients with advanced disease (AI > 6.0 [p = 0.002]; EDSS > 4.0 [p = 0.02]; MSSS > 4.8 [p = 0.01]).

    In the subgroup of patients having Gd-enhancing MRI lesions (n = 11), correlation between the volume of enhancement and CSF NOx was found (r = 0.74, p = 0.01).

    In the follow-up study, patients with disability progression had higher baseline CSF NOx levels than those who were stable on EDSS (p = 0.02) or AI (p = 0.03).

    A positive correlation was found between baseline CSF NOx and the change in MR T2-weighted lesion load (r = 0.4, p = 0.03).

    Conclusions
    CSF Nitrite and Nitrate levels were increased in mildly disabled patients with MS and found to correlate with the volume of Gd-enhanced lesions on MRI.

    Raised baseline CSF NOx was associated with clinical and MRI progression in MS patients over 3-year follow-up.



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