The Iron-Oxidative Stress Nexus in Multiple Sclerosis: Pathways to Neurodegeneration and Therapeutic Insights

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination, neurodegeneration, and axonal dysfunction. Recent research has shed light on the intricate relationship between iron accumulation, reactive oxygen species (ROS), reactive nitrogen species (RNS), and the progression of MS. Iron's role in MS pathology, its accumulation within the brain, and its contribution to oxidative stress form a critical axis influencing disease dynamics and therapeutic strategies.

Iron Accumulation in MS

Iron plays a crucial part in the pathophysiology of MS. Elevated levels of iron in the brain, particularly in areas of neurodegeneration and lesion sites, have been consistently observed in MS patients. Iron's contribution to MS pathology is multifaceted, involving its role in amplifying oxidative stress, affecting mitochondrial function, and influencing neurodegeneration. Iron's redox-active nature makes it a potent catalyst for the production of ROS and RNS, exacerbating cellular damage through oxidative stress mechanisms​​.

ROS and RNS in MS

ROS and RNS are highly reactive molecules that can cause significant damage to cellular components, including DNA, proteins, and lipids. In the context of MS, the production of ROS and RNS is closely linked to inflammation and immune system activity within the central nervous system. Chronic inflammation in MS results in elevated levels of ROS and RNS, contributing to mitochondrial injury and exacerbating neurodegenerative processes​​.

Ferroptosis in MS

Ferroptosis, an iron-catalyzed form of cell death driven by lipid peroxidation, has emerged as a critical player in the pathology of MS. It is distinct from other forms of cell death due to its reliance on iron and its unique mechanism involving the peroxidation of polyunsaturated fatty acids. Research indicates that ferroptosis contributes significantly to demyelination and disease progression in both relapsing-remitting and progressive forms of MS. The accumulation of iron, particularly ferrous iron (Fe 2+), in lesion sites and its role in driving ferroptosis highlight the potential of targeting iron homeostasis and lipid peroxidation as therapeutic strategies for MS​​.

Therapeutic Implications

The intricate relationship between iron accumulation, ROS/RNS production, and ferroptosis in MS underscores the need for therapeutic strategies that address these interconnected pathways. Antioxidants, iron chelators, and inhibitors of lipid peroxidation are among the potential therapeutic approaches that could mitigate iron-related oxidative damage and improve outcomes for MS patients. Understanding the molecular mechanisms underlying iron accumulation and its impact on ROS/RNS dynamics and ferroptosis is critical for developing targeted therapies that could slow disease progression and promote neuroprotection in MS.

Conclusion

The association between iron accumulation, oxidative stress, and ferroptosis in MS provides valuable insights into the disease's underlying mechanisms and offers new avenues for therapeutic intervention. By targeting the complex interplay between iron metabolism and oxidative stress pathways, future research holds the promise of developing more effective treatments for MS, aiming to reduce neurodegeneration and enhance the quality of life for patients.

Reference:

Stephenson, E., Nathoo, N., Mahjoub, Y., Dunn, J. F., & Yong, V. W. (2014). Iron in multiple sclerosis: roles in neurodegeneration and repair. Nature Reviews Neurology, 10(8), 459-468.
Yong, H. Y., & Yong, V. W. (2022). Mechanism-based criteria to improve therapeutic outcomes in progressive multiple sclerosis. Nature Reviews Neurology, 18(1), 40-55.
Van San, E., Debruyne, A. C., Veeckmans, G., Tyurina, Y. Y., Tyurin, V. A., Zheng, H., ... & Vanden Berghe, T. (2023). Ferroptosis contributes to multiple sclerosis and its pharmacological targeting suppresses experimental disease progression. Cell Death & Differentiation, 30(9), 2092-2103.