Abstract
Oxidative status may play a role in chronic inflammation and neurodegeneration which are considered critical etiopathogenetic factors in Multiple Sclerosis (MS), both in the early phase of the disease and in the progressive one. The aim of this study is to explore oxidative status related to iron metabolism in peripheral blood of stable Relapsing-Remitting MS with low disability. We studied 60 Relapsing-Remitting MS patients (age 37.2 ± 9.06, EDSS median 1.0), and 40 healthy controls (age 40.3 ± 10.86). We measured total hydroperoxides (dROMs test) and Total Antioxidant Status (TAS), along with the iron metabolism biomarkers: Iron (Fe), ferritin (Ferr), transferrin (Tf), transferrin saturation (Tfsat), and ceruloplasmin (Cp) panel biomarkers [concentration (iCp) and enzymatic activity (eCp), copper (Cu), ceruloplasmin specific activity (eCp:iCp), copper to ceruloplasmin ratio (Cu:Cp), non-ceruloplasmin copper (nCp-Cu)]. We computed also the Cp:Tf ratio as an index of oxidative stress related to iron metabolism. We found lower TAS levels in MS patients than in healthy controls (CTRL) and normal reference level and higher dROMs and Cp:Tf ratio in MS than in healthy controls. Cp and Cu were higher in MS while biomarkers of iron metabolism were not different between patients and controls. Both in controls and MS, dROMs correlated with iCp (CTRL r = 0.821, p < 0.001; MS r = 0.775 p < 0.001) and eCp (CTRL r = 0.734, p < 0.001; MS r = 0.820 p < 0.001). Moreover, only in MS group iCp correlated negatively with Tfsat (r = -0.257, p = 0.047). Dividing MS patients in “untreated” group and “treated” group, we found a significant difference in Fe values [F(2, 97) = 10.136, p < 0.001]; in particular “MS untreated” showed higher mean values (mean = 114.5, SD = 39.37 μg/dL) than CTRL (mean 78.6, SD = 27.55 μg/dL p = 0.001) and “MS treated” (mean = 72.4, SD = 38.08 μg/dL; p < 0.001). Moreover, “MS untreated” showed significantly higher values of Cp:Tf (mean = 10.19, SD = 1.77∗10-2; p = 0.015), than CTRL (mean = 9.03, SD = 1.46 ∗10-2). These results suggest that chronic oxidative stress is relevant also in the remitting phase of the disease in patients with low disability and short disease duration. Therefore, treatment with antioxidants may be beneficial also in the early stage of the disease to preserve neuronal reserve.
Highlights
Multiple sclerosis (MS) is a chronic immune-mediated condition that can affect the brain and the spinal cord and is characterized by a relapsing remitting (RRMS) course eventually followed by secondary progression (SPMS) or gradual progression of disability since the beginning
Cp has been recognized as marker of inflammation in systemic pathologies (Göçmen et al, 2008; Tang et al, 2012) and we found that the Cp:Tf ratio is elevated in Alzheimer’s disease (Squitti et al, 2010; Siotto et al, 2016), in stroke (Altamura et al, 2009; Squitti et al, 2018b) and in subacute post-stroke patients affected by neuropathic pain (Siotto et al, 2017), where it correlates with the clinical status
TAS was significantly lower in patients than in controls (MS mean = 1.24, standard deviation (SD) = 0.14 vs. control group (CTRL) mean = 1.39, SD = 0.13 mmol/L; p = 0.001) and lower than normal reference range indicated by the manufacturer (1.30–1.77 mmol/L)
Summary
Multiple sclerosis (MS) is a chronic immune-mediated condition that can affect the brain and the spinal cord and is characterized by a relapsing remitting (RRMS) course eventually followed by secondary progression (SPMS) or gradual progression of disability since the beginning (primary progressive MS – PPMS). Consolidated biomarkers of chronic inflammation in MS are lacking, many studies have identified oxidative stress markers as promising to estimate peripheral inflammation in MS since inflammation leads to oxidative stress and vice-versa (Naidoo and Knapp, 1992; Karg et al, 1999; Besler and Comoglu, 2003; Ferretti et al, 2005; Koch et al, 2006; Alimonti et al, 2007; Ortiz et al, 2009, 2013; Ghabaee et al, 2010; Ristori et al, 2011; Miller et al, 2012; Oliveira et al, 2012; Tasset et al, 2012) The majority of these studies have demonstrated an increase of peripheral inflammation in the progressive forms of MS or during a relapse; few of them have suggested that oxidative stress and antioxidant capacity are elevated in RRMS during the remitting phase (Ferretti et al, 2005; Koch et al, 2006; Miller et al, 2012; Oliveira et al, 2012)
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