Oxidative and nitrative stress and pro-inflammatory cytokines in Mucopolysaccharidosis type II patients: effect of long-term enzyme replacement therapy and relation with glycosaminoglycan accumulation

Abstract

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disease caused by a deficient activity of iduronate-2-sulfatase, leading to abnormal accumulation of glycosaminoglycans (GAG). The main treatment for MPS II is enzyme replacement therapy (ERT). Previous studies described potential benefits of six months of ERT against oxidative stress in patients. Thus, the aim of this study was to investigate oxidative, nitrative and inflammatory biomarkers in MPS II patients submitted to long term ERT. It were analyzed urine and blood samples from patients on ERT (mean time: 5.2years) and healthy controls. Patients presented increased levels of lipid peroxidation, assessed by urinary 15-F2t-isoprostane and plasmatic thiobarbituric acid-reactive substances. Concerning to protein damage, urinary di-tyrosine (di-Tyr) was increased in patients; however, sulfhydryl and carbonyl groups in plasma were not altered. It were also verified increased levels of urinary nitrate+nitrite and plasmatic nitric oxide (NO) in MPS II patients. Pro-inflammatory cytokines IL-1β and TNF-α were increased in treated patients. GAG levels were correlated to di-Tyr and nitrate+nitrite. Furthermore, IL-1β was positively correlated with TNF-α and NO. Contrastingly, we did not observed alterations in erythrocyte superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities, in reduced glutathione content and in the plasmatic antioxidant capacity. Although some parameters were still altered in MPS II patients, these results may suggest a protective role of long-term ERT against oxidative stress, especially upon oxidative damage to protein and enzymatic and non-enzymatic defenses. Moreover, the redox imbalance observed in treated patients seems to be GAG- and pro-inflammatory cytokine-related.

Characterization of Fluid Biomarkers Reveals Lysosome Dysfunction and Neurodegeneration in Neuronopathic MPS II Patients

“…In addition to showing lysosomal dysfunction, MPS II mouse brains (as well MPS I and III) show widespread neuroinflammation and astrogliosis, as indicated by increased markers of gliosis [ 11 , 12 , 13 ], and increased inflammatory cytokines [ 12 ]. This is in agreement with the observation that plasma and CSF from MPS I patients showed significantly elevated inflammatory cytokines, including IL-1b, TNF-a, MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF [ 14 , 15 , 16 ].…”

Biomarkers in patients with mucopolysaccharidosis type II and IV

“…TNF-α was associated with pain and physical disability, despite treatment with ERT and/or HSCT [12]. Jacques et al also measured pro-inflammatory cytokines and showed the elevation of TNF-α and IL-1β in plasma from MPS II patients with ERT, compared to controls [13]. Donida et al also indicated that the plasma levels of IL-6 were higher in MPS IVA patients under ERT, compared with controls [14].…”

Effect of glycosaminoglycans accumulation on the non-oxidative sulfur metabolism in mouse model of Sanfilippo syndrome, type B

“…Nevertheless, the increase in cysteine level contributes to an increase in the content of cell reductants, such as glutathione or thioredoxin, that can effectively counteract a locally occurring oxidative stress (Nagahara et al, 2007). Jacquez and others (Jacquez et al, 2016) observed that the disturbance of redox balance could be GAGs-and pro-inflammatory cytokine-related. We documented the redox imbalance in two cases.…”