CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis

Rejdak, Konrad; Eikelenboom, Merijn; Petzold, Axel; Thompson, Edward H.; Stelmasiak, Zbigniew; Lazeron, R.H.C.; Barkhof, Frederik; Polman, Chris H.; Uitdehaag, Bernard M. J.; Giovannoni, Gavin

doi:10.1212/01.wnl.0000142043.32578.5d

Cited by 114 publications

(73 citation statements)

References 45 publications

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“…The partial reduction of NO (4) and TNF-a (5) synthesis prevents the development of EAE. Furthermore, NO metabolites detected in the cerebrospinal fluid of MS patients are associated with the progression of the disease (6). These data indicate an important role of NO and TNF-a in the onset of MS.…”

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confidence: 69%

Ceramide Synthase 6 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis

Schiffmann

Ferreiròs

Birod

et al. 2012

The Journal of Immunology

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Ceramides are mediators of apoptosis and inflammatory processes. In an animal model of multiple sclerosis (MS), the experimental autoimmune encephalomyelitis (EAE) model, we observed a significant elevation of C16:0-Cer in the lumbar spinal cord of EAE mice. This was caused by a transiently increased expression of ceramide synthase (CerS) 6 in monocytes/macrophages and astroglia. Notably, this corresponds to the clinical finding that C16:0-Cer levels were increased 1.9-fold in cerebrospinal fluid of MS patients. NO and TNF-α secreted by IFN-γ–activated macrophages play an essential role in the development of MS. In murine peritoneal and mouse-derived RAW 264.7 macrophages, IFN-γ–mediated expression of inducible NO synthase (iNOS)/TNF-α and NO/TNF-α release depends on upregulation of CerS6/C16:0-Cer. Downregulation of CerS6 by RNA interference or endogenous upregulation of C16:0-Cer mediated by palmitic acid in RAW 264.7 macrophages led to a significant reduction or increase in NO/TNF-α release, respectively. EAE/IFN-γ knockout mice showed a significant delay in disease onset accompanied by a significantly less pronounced increase in CerS6/C16:0-Cer, iNOS, and TNF-α compared with EAE/wild-type mice. Treatment of EAE mice with l-cycloserine prevented the increase in C16:0-Cer and iNOS/TNF-α expression and caused a remission of the disease. In conclusion, CerS6 plays a critical role in the onset of MS, most likely by regulating NO and TNF-α synthesis. CerS6 may represent a new target for the inhibition of inflammatory processes promoting MS development.

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confidence: 69%

Ceramide Synthase 6 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis

Schiffmann

Ferreiròs

Birod

et al. 2012

The Journal of Immunology

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“…Nitric oxide is difficult to be measured directly and NO level is mainly measured by its nitroderivatives in CSF or peripheral plasma. Several immunohistochemical studies have shown 1.5 to 3 times higher NO endproducts levels in MS patients compared with controls (Acar et al, 2003;Rejdak et al, 2004) and such increased NO can be diffuse and distal to the lesions (Moncada and Bolanos, 2006;Smith and Lassmann, 2002). Although it is difficult to differentiate these two pathological processes in vivo using our techniques, we note that the CMRO 2 reduction in MS patients was about 20% (compared with control subjects), which was much greater than the atrophic change (B2%) or lesion volume (B0.5%).…”

Section: Discussionmentioning

confidence: 99%

Characterizing Brain Oxygen Metabolism in Patients with Multiple Sclerosis with T2-Relaxation-Under-Spin-Tagging MRI

Zhang

Lu³

et al. 2012

J Cereb Blood Flow Metab

143

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In this study, venous oxygen saturation and oxygen metabolic changes in multiple sclerosis (MS) patients were assessed using a recently developed T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI), which measures the superior sagittal venous sinus blood oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO 2 ), an index of global oxygen consumption. Thirty patients with relapsing-remitting MS and 30 age-matched healthy controls were studied using TRUST at 3 T MR. The mean expanded disability status scale (EDSS) of the patients was 2.3 (range, 0 to 5.5). We found significantly increased Yv (P < 0.0001) and decreased CMRO 2 (P = 0.003) in MS patients (mean±s.d.: 65.9%±5.1% and 138.8±35.4 lmol per 100 g per minute) as compared with healthy control subjects (60.2% ± 4.0% and 180.2 ± 24.8 lmol per 100 g per minute, respectively), implying decrease of oxygen consumption in MS. There was a significant positive correlation between Yv and EDSS and between Yv and lesion load in MS patients (n = 30); on the contrary, there was a significant negative correlation between CMRO 2 and EDSS and between CMRO 2 and lesion load (n = 12). There was no correlation between Yv and brain atrophy measures. This study showed preliminary evidence of the potential utility of TRUST in global oxygen metabolism. Our results of significant underutilization of oxygen in MS raise important questions regarding mitochondrial respiratory dysfunction and neurodegeneration of the disease.

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“…Cerebrospinal fluid (CSF) studies have confirmed the findings of increased inflammation, 13,14 axonal damage, 15,16 demyelination 17 and oxidative stress 18,19 in progressive MS. However, to our knowledge no studies have explored whether these CSF biomarkers are related in progressive MS. On this background we hypothesised that biomarkers of inflammation, axonal damage and demyelination are increased in secondary progressive MS (SPMS) and primary progressive MS (PPMS) and that these biomarkers correlate.…”

Section: Introductionmentioning

confidence: 88%

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

et al. 2012

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Background:The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. Objectives: To study cerebrospinal fluid (CSF) biomarkers and clarify whether inflammation and axonal damage are associated in progressive MS. Methods: Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing-remitting (RRMS) and 20 non-inflammatory neurological disease (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF followup after one year. Results: Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13 was increased in RRMS and SPMS patients. Biomarkers of axonal damage (NFL) and demyelination (MBP) were increased in all MS patients. In progressive MS patients CSF levels of osteopontin and CXCL13 correlated with NFL while osteopontin and MMP9 correlated with MBP. MBP8298 treatment did not affect the levels of the biomarkers after one year of treatment. All biomarkers were continuously increased after one year of follow-up except MBP, which decreased. Conclusion: CSF biomarkers of inflammation, axonal damage and demyelination are continuously increased in progressive MS patients and correlate. These findings parallel pathology studies, emphasise a relationship between inflammation, axonal damage and demyelination and support the use of CSF biomarkers in progressive MS clinical trials.

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CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis

Abstract: 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.

Cited by 114 publications

References 45 publications

Ceramide Synthase 6 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis

Ceramide Synthase 6 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis

Characterizing Brain Oxygen Metabolism in Patients with Multiple Sclerosis with T2-Relaxation-Under-Spin-Tagging MRI

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

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