Abstract
Introduction: Oxidative stress is implicated in the pathophysiology of multiple sclerosis (MS). Despite this, the potential of oxidative stress responses as a biomarker of MS disease activity and therapeutic response to disease modifying therapy (DMT) has not been explored. To evaluate their potential as MS biomarkers, plasma protein levels and relative peripheral blood mononuclear cell (PBMC) messenger ribonucleic acid (mRNA) expression of two master regulators of antioxidant response; nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α); downstream antioxidant enzymes superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPx1) and catalase, and plasma end products of oxidation 4-hydroxynonenal (4-HNE), 8-hydroxy-2-deoxyguanosine (8-OHdG) and protein carbonyls were measured in people with MS (pwMS). The peripheral blood oxidative stress profile was compared between pwMS and healthy donors, in pwMS commencing DMT with dimethyl fumarate (DMF), ocrelizumab and natalizumab, and in patients with relapsing-remitting MS (RRMS) versus progressive MS (PMS) phenotypes. Peripheral blood levels of these oxidative stress markers were correlated with established clinical measures of disease; Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC) and Multiple Sclerosis Impact Scale (MSIS-29).Methods: A 12-month, prospective, observational study was performed, measuring markers of oxidative stress in peripheral blood from pwMS. Plasma concentrations of Nrf2, PGC-1α, SOD1, GPx1, 4-HNE, 8-OHdG and protein carbonyls were measured using enzyme-linked immunosorbent assay (ELISA). Plasma catalase activity was measured using a catalase activity assay. Relative expression of NFE2L2 (Nrf2), PPARGC1A (PGC-1α), SOD1, GPX1 and CAT (catalase) mRNA was measured using real-time quantitative polymerase chain reaction (PCR). The results were analysed using multiple regression models.
Results: A total of 78 participants (53 RRMS, 11 PPMS and 14 with secondary progressive (SPMS)) and 40 healthy control subjects were recruited; 12 participants commencing DMT with DMF, 12 participants with ocrelizumab and 7 participants with natalizumab were included in the study. Oxidative stress responses were variable and inconsistent, both within and between individuals. Despite this, there are strong signals to indicate that markers of oxidative stress were increased in the peripheral blood of pwMS, particularly those with SPMS. Introduction of disease modifying therapies was associated with increased antioxidant responses.
Conclusions: Data from this study supports a role for dysregulation of oxidative stress responses in the pathogenesis of MS. However, based on the present model, their potential as clinically useful biomarkers in MS is limited. The degree of variability within and between individuals is likely to preclude use of the markers examined as clinical biomarkers of disease phenotype and DMT response. Oxidative stress responses are complex and challenging to measure. Interpreting individual components of intricate redox systems is fraught with difficulty. Despite this, there are strong signals that warrant further evaluation, and support a potential role for a composite panel of oxidative stress biomarkers that measures the oxidative stress profile as a whole, increasing the predictive value of these oxidative stress biomarkers. Further investigation of the underlying oxidative processes is likely to improve understanding of the pathophysiology of MS and identify potential novel therapeutic interventions.
| Date of Award | 9 Dec 2025 |
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| Original language | English |
| Awarding Institution |
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| Sponsors | Sanofi S.A. |
| Supervisor | Claire M Rice (Supervisor) & Neil Scolding (Supervisor) |