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Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology
Gerty Schreibelt1, Jack van Horssen, Saskia van Rossum
1Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Abstract:
Reactive oxygen species contribute to the formation and persistence of multiple sclerosis (MS) lesions by acting on distinct pathological processes. To counteract the detrimental effects of ROS the central nervous system is endowed with a protective mechanism consisting of enzymatic and non-enzymatic antioxidants. Expression of most antioxidant enzymes is regulated through the transcription factor nuclear factor-E2-related factor (Nrf2) and antioxidant response elements (ARE) in the genes encoding enzymatic antioxidants and is induced by oxidative stress. In brain tissue of MS patients, enhanced expression of Nrf2/ARE-regulated antioxidants is suggestive of the occurrence of oxidative stress in these lesions. Antioxidant therapy may therefore represent an attractive treatment of MS. Several studies have shown that antioxidant therapy is beneficial in vitro and in vivo in animal models for MS. However, the use of exogenous antioxidants for MS treatment has drawbacks, as large amounts of antioxidants are required to achieve functional antioxidant levels in the central nervous system. Therefore, the induction of endogenous antioxidant enzymes by activators of the Nrf2/ARE pathway may be an interesting approach to obtain sufficient levels of antioxidants to interfere with pathological processes underlying MS lesion formation. In this review we summarize and discuss the biological role, regulation and potential therapeutic effects of endogenous antioxidant enzymes in MS. We propose that antioxidants may inhibit the development and progression of MS lesions and may therefore represent an attractive therapeutic target for the treatment of MS and other oxidative stress-related neurological diseases.
Insights
Reactive oxygen species contribute to multiple sclerosis (MS) lesions. Activating endogenous antioxidant enzymes via the Nrf2/ARE pathway offers a promising therapeutic strategy for MS treatment.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Reactive oxygen species (ROS) play a significant role in the pathogenesis of multiple sclerosis (MS), contributing to lesion formation and persistence.
- The central nervous system possesses endogenous antioxidant systems, including enzymatic and non-enzymatic antioxidants, to counteract oxidative stress.
- The nuclear factor-E2-related factor (Nrf2) pathway regulates the expression of many antioxidant enzymes through antioxidant response elements (ARE).
Purpose of the Study:
- To review the biological role, regulation, and therapeutic potential of endogenous antioxidant enzymes in the context of multiple sclerosis.
- To explore the Nrf2/ARE pathway as a target for inducing endogenous antioxidant defenses against MS pathology.
- To discuss the advantages of activating endogenous antioxidant mechanisms over exogenous antioxidant administration for MS treatment.
Main Methods:
- Literature review summarizing existing research on oxidative stress, Nrf2/ARE pathway, and antioxidant therapies in MS.
- Analysis of studies investigating the effects of antioxidant interventions in vitro and in animal models of MS.
- Discussion of the mechanisms by which endogenous antioxidants may interfere with MS lesion development.
Main Results:
- Enhanced expression of Nrf2/ARE-regulated antioxidants in MS brain tissue indicates significant oxidative stress.
- In vitro and in vivo studies demonstrate the beneficial effects of antioxidant therapy in experimental models of MS.
- Exogenous antioxidant administration requires high doses and faces challenges in achieving effective CNS concentrations.
Conclusions:
- Activating the endogenous Nrf2/ARE antioxidant pathway presents a promising therapeutic strategy for MS.
- Inducing endogenous antioxidant enzymes may provide sufficient levels to counteract MS-related oxidative damage.
- Antioxidant strategies targeting endogenous defenses hold potential for treating MS and other neurological diseases associated with oxidative stress.
