Modulation of Paraoxonase 1 Activity and Asymmetric Dimethylarginine by Immunomodulatory Therapies in Multiple Sclerosis

TL;DR

This study explores how antioxidant enzyme PON1 and ADMA levels change in MS patients and how they are affected by different treatments.

Contribution

The study reveals how immunomodulatory therapies influence PON1 activity and ADMA levels in multiple sclerosis subtypes.

Findings

PON1 arylesterase activity was significantly reduced in MS patients compared to controls.

Immunomodulatory therapies, especially interferon, significantly altered PON1 activity over time.

ADMA levels were lower in MS patients and varied among treatment groups.

Abstract

Background: Neurodegeneration is present from the earliest stages of multiple sclerosis [MS], and oxidative stress together with mitochondrial dysfunction are key contributors to neuronal injury and disease progression. Objective: To investigate the role of the antioxidant enzyme paraoxonase 1 (PON1) and serum asymmetric dimethylarginine (ADMA) levels in MS across different disease subtypes and immunomodulatory treatments. Methods: Serum lipid levels and PON1 activity were measured and compared by disease subtype and treatment in a single-center MS cohort (N = 262; CIS = 10, RRMS = 208, PPMS = 19, SPMS = 25; 110 untreated, 152 treated) and in 91 healthy controls. ADMA levels were assessed in sera from 79 MS patients (19 untreated, 60 treated) and 31 age-matched controls. Results: Median serum paraoxonase (PON) and arylesterase (ARE) activity levels were 83.8 and 127.2 IU/L in MS patients versus 85.9 and 136.9 IU/L in controls, with no significant difference for PON (p = 0.191) but a significant reduction in ARE [p = 0.003]. PON activity differed significantly among disease subtypes (p = 0.023), with the highest levels in CIS. PON and ARE activity also varied across treatment groups (p = 0.038 and p = 0.034, respectively), with longitudinal analysis indicating a measurable effect of immunomodulatory therapy on PON activity at 10 years (p = 0.0136). Significant differences in enzyme activity were observed between untreated and interferon-treated patients (PON p = 0.0055, ARE p = 0.0001), with trends toward differences in ARE under natalizumab and fingolimod. ADMA levels were lower in MS patients than controls (p < 0.0001) and differed among treatment subgroups (natalizumab, dimethyl fumarate, glatiramer acetate, untreated RRMS). Conclusions: PON1 activity and ADMA levels differ between MS subgroups and under immunomodulatory treatments. Long-term therapy was associated with increased PON1 activity, while highly effective immunomodulators reduced ADMA levels. These changes may contribute to the treatment-related reduction in disease activity and attenuation of neurodegenerative processes in MS.

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