Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by ¹H magnetic resonance chemical shift imaging at 3 T

Abstract

Background Disability levels for patients with secondary progressive multiple sclerosis (SPMS) often worsen despite a stable MRI T2 lesion burden. The presence of oxidative stress in the absence of measurable inflammation could help explain this phenomenon. In this study, the assessment of an in vivo marker of oxidative stress, cerebral glutathione (GSH), using magnetic resonance chemical shift imaging (CSI) is described, and GSH levels were compared in patients with SPMS and healthy controls. Objective To assess whether GSH, a key antioxidant in the brain, is lower in the SPMS patients compared to matched controls. Methods Seventeen patients with SPMS (Expanded Disability Status Scale = 4.0–7.0; length of MS diagnosis = 19.4±7 years) and 17 age- and gender-matched healthy controls were studied. GSH levels were measured in the fronto-parietal regions of the brain using a specially designed magnetic resonance spectroscopy technique, CSI of GSH, at 3T. Results The levels of GSH were lower for SPMS patients than for controls, the largest reduction (18.5%) being in the frontal region (p=0.001). Conclusion The lower GSH levels in these patients indicate the presence of oxidative stress in SPMS. This process could be at least partially responsible for ongoing functional decline in SPMS.

Peripheral oxidative stress in relapsing–remitting multiple sclerosis

“…This runs counter to the findings reported in clinical and experimental studies of nerve tissue and cerebrospinal fluid [28][29][30][31]; Di Giussepe et al also observed no statistically-significant difference in GSH levels between RR-MS patients and healthy controls [32]. This apparent discrepancy may be due to the nature of the sample (tissue, cerebrospinal fluid, plasma or erythrocytes), to differences in the study situation (experimental models and clinical studies with different characteristics) and/or to patient-specific features.…”

Redox regulation of cellular stress response in multiple sclerosis

“…A variety of studies, supporting a role for oxidative stress in MS, indicate that endogenous antioxidants are decreased in MS, and damage to mitochondria induced by lipid peroxidation can lead to further ROS generation [35][36][37][38][39]. However, up-regulation of antioxidants in astrocytes and macrophages in active MS lesions [30] as well as in leukocytes suggests that endogenous protection from oxidative damage could limit the deleterious consequences of the oxidative stress per se [40]. Interestingly, exogenously administrated antioxidants have shown some beneficial effects in animal studies of MS but no clinical studies support the use of such therapy [41][42][43][44].…”

Fumarates Promote Cytoprotection of Central Nervous System Cells against Oxidative Stress via the Nuclear Factor (Erythroid-Derived 2)-Like 2 Pathway

“…Elucidation of this pathway suggests a potential role for cell type-specific neuroprotective responses and is consistent with the astrocyte data presented here. It is clear that increasing cellular GSH levels in the CNS could have a meaningful therapeutic impact on MS, because reduced brain GSH levels have been reported in patients with MS, as measured by magnetic resonance spectroscopy (Srinivasan et al, 2010;Choi et al, 2011). Therapies in clinical trials for MS, such as BG-12, which is an oral therapeutic containing DMF as the active ingredient (which is quantitatively converted to MMF after oral DMF delivery), could increase cellular GSH levels ( Fig.…”