Siotto Mariacristina, Filippi Maria Maddalena, Simonelli Ilaria, Landi Doriana, Ghazaryan Anna, Vollaro Stefano, Ventriglia Mariacarla, Pasqualetti Patrizio, Rongioletti Mauro Ciro Antonio, Squitti Rosanna, Vernieri Fabrizio
IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy.
Fatebenefratelli Foundation for Health Research and Education, AFaR Division, Rome, Italy.
Front Neurosci. 2019 Feb 11;13:86. doi: 10.3389/fnins.2019.00086. eCollection 2019.
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 = 0.821, < 0.001; MS = 0.775 < 0.001) and eCp (CTRL = 0.734, < 0.001; MS = 0.820 < 0.001). Moreover, only in MS group iCp correlated negatively with Tfsat ( = -0.257, = 0.047). Dividing MS patients in "untreated" group and "treated" group, we found a significant difference in Fe values [(2, 97) = 10.136, < 0.001]; in particular "MS untreated" showed higher mean values (mean = 114.5, = 39.37 μg/dL) than CTRL (mean 78.6, = 27.55 μg/dL = 0.001) and "MS treated" (mean = 72.4, = 38.08 μg/dL; < 0.001). Moreover, "MS untreated" showed significantly higher values of Cp:Tf (mean = 10.19, = 1.7710; = 0.015), than CTRL (mean = 9.03, = 1.46 10). 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.
氧化状态可能在慢性炎症和神经退行性变中起作用，而慢性炎症和神经退行性变被认为是多发性硬化症（MS）关键的病因发病因素，在疾病的早期阶段和进展期均是如此。本研究的目的是探讨低残疾程度的稳定复发缓解型MS患者外周血中与铁代谢相关的氧化状态。我们研究了60例复发缓解型MS患者（年龄37.2±9.06，扩展残疾状态量表（EDSS）中位数为1.0）和40名健康对照者（年龄40.3±10.86）。我们测量了总氢过氧化物（dROMs检测）和总抗氧化状态（TAS），以及铁代谢生物标志物：铁（Fe）、铁蛋白（Ferr）、转铁蛋白（Tf）、转铁蛋白饱和度（Tfsat）和铜蓝蛋白（Cp）组生物标志物[浓度（iCp）和酶活性（eCp）、铜（Cu）、铜蓝蛋白比活性（eCp:iCp）、铜与铜蓝蛋白比值（Cu:Cp）、非铜蓝蛋白铜（nCp-Cu）]。我们还计算了Cp:Tf比值作为与铁代谢相关的氧化应激指标。我们发现MS患者的TAS水平低于健康对照者（CTRL）和正常参考水平，且MS患者的dROMs和Cp:Tf比值高于健康对照者。MS患者的Cp和Cu较高，而患者和对照者之间的铁代谢生物标志物无差异。在对照者和MS患者中，dROMs均与iCp相关（对照者r = 0.821，P < 0.001；MS患者r = 0.775，P < 0.001）以及与eCp相关（对照者r = 0.734，P < 0.001；MS患者r = 0.820，P < 0.001）。此外，仅在MS组中，iCp与Tfsat呈负相关（r = -0.257，P = 0.047）。将MS患者分为“未治疗”组和“治疗”组，我们发现Fe值存在显著差异[F(2, 97) = 10.136，P < 0.001]；特别是“未治疗的MS”组的平均值（均值 = 114.5，标准差 = 39.37 μg/dL）高于对照者（均值78.6，标准差 = 27.55 μg/dL，P = 0.001）和“治疗的MS”组（均值 = 72.4，标准差 = 38.08 μg/dL；P < 0.001）。此外，“未治疗的MS”组的Cp:Tf值显著高于对照者（均值 = 10.19，标准差 = 1.7710；P = 0.015）（对照者均值 = 9.03，标准差 = 1.46×10）。这些结果表明，慢性氧化应激在低残疾程度和疾病病程较短的患者的疾病缓解期也具有相关性。因此，抗氧化剂治疗在疾病早期可能也有益，以保留神经储备。
