Nitrosative Stress Molecules in Multiple Sclerosis: A Meta-Analysis

Abstract

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system of unknown etiology. As it is still a diagnosis of exclusion, there is an urgent need for biomarkers supporting its diagnosis. Increasing evidence suggests that nitrosative stress may play a pivotal role in the pathogenesis of MS. However, previous reports supporting the role of nitrosative stress molecules as disease biomarkers are inconsistent overall. We therefore systematically analyzed the existing literature to compare the serum and cerebrospinal fluid (CSF) levels of nitrite/nitrate in MS patients with those in patients with noninflammatory other neurological diseases (NIOND) and healthy controls (HC), respectively. We searched the PubMed database and included original articles investigating nitrite/nitrate levels in MS patients and NIOND patients or HC based on predefined selection criteria. Effect sizes were estimated by the standardized mean difference using a random effects model. Our results suggest that MS is associated with higher nitrite/nitrate levels within the CSF compared with patients with NIOND (SMD of 1.51; 95% CI: 0.72, 2.30; p = 0.0008). Likewise, nitrite/nitrate in the CSF of MS patients trends towards increased levels compared with those of HC but does not reach statistical significance (SMD of 3.35; 95% CI: −0.48, 7.19; p = 0.07). Measurement of nitrite/nitrate in the CSF might be a valuable tool facilitating the differentiation of MS and NIOND. Further studies with more homogeneous study criteria are needed to corroborate this hypothesis.

The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis

“…Nevertheless, in contrast to the serum, CSF NOx levels did not significantly differ between RRMS and Soma patients, indicating that the diagnostic value of NOx is more pronounced in the serum than in the CSF. Notably, even though the investigated groups are only partly comparable, this is a not in line with the results of our meta-analysis [10]. Pathophysiologically, however, this might simply point to the pivotal contribution of the peripheral immune system to the inflammatory processes in MS. On the other hand, we found a positive correlation between the EDSS and overall CSF NOx levels.…”

“…Our previous meta-analysis found significantly increased CSF NOx levels in RRMS patients compared to NIOND [10]. We therefore measured CSF NOx levels in 26 RRMS compared to 12 Soma patients, but did not find significant differences between the two groups (Figure 2A).…”

“…Pathophysiologically, inflammatory attacks mediated by autoreactive innate and adaptive immune cells together with a dysregulated humoral immune response contribute to demyelination and axonal damage [8,9]. There is increasing evidence that NO produced by immune or CNS-resident cells is involved in the pathogenesis of MS [10]. Mechanistically, the release of proinflammatory cytokines induces iNOS expression in reactive microglia, astrocytes, and macrophages, which contributes to the synthesis of NO [1].…”

“…In comparison to healthy controls (HC), no statistically significant differences of NOx levels in serum or CSF could be detected in MS patients. However, many of the included studies did not distinguish between the different clinical subtypes of MS, included pre-treated patients, and inclusion criteria for the NIOND and the HC groups varied [10]. In this follow-up study, we therefore aimed to analyze the serum and CSF NOx levels in clinically well-defined cohorts of treatment-naïve patients with RRMS and PPMS compared to patients with somatic symptom disorder (Soma) to assess the potential of NOx as biomarkers facilitating the diagnosis of MS.…”

The Study of Association between Serum NADPH Oxidase Concentrations and Iron Metabolism in Relapsing Remitting Multiple Sclerosis

“…amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease) Inflammation and neurodegeneration are mutually dependent phenomena [18]. The cause of multiple sclerosis (MS) remains a mystery [19]. Several studies have shown that tiny, oxygen-derived molecules called reactive oxygen species (ROS) may have a role in the pathophysiology of multiple sclerosis [1].…”