Multiple sclerosis (MS) is a complex neurological disease characterized by damage to the protective covering of nerve fibers in the central nervous system, called myelin. This damage disrupts communication between the brain and the rest of the body, leading to symptoms like muscle weakness, vision problems, and impaired coordination. One of the critical factors increasingly recognized in the development and progression of MS is oxidative stress, a biological condition where harmful molecules called reactive oxygen species (ROS) overwhelm the body’s natural antioxidant defenses.
Oxidative stress occurs when there is an imbalance between the production of ROS and the body’s ability to neutralize them. ROS are chemically reactive molecules containing oxygen, such as free radicals and peroxides. While ROS are normal byproducts of cellular metabolism and even play roles in cell signaling, excessive ROS can damage cells by attacking lipids, proteins, and DNA. In the context of MS, this oxidative damage is particularly harmful to neurons and the cells responsible for producing myelin, called oligodendrocytes.
One of the key connections between MS and oxidative stress involves iron metabolism. Iron is essential for many cellular functions, but when present in excess, it can catalyze the formation of ROS through chemical reactions like the Fenton reaction. In MS patients, abnormal iron accumulation has been observed in certain brain regions, such as the gray matter, while iron levels are reduced in white matter areas. This dysregulation of iron contributes to oxidative stress by increasing ROS production, which in turn damages neurons, oligodendrocytes, and even the blood-brain barrier—a critical structure that protects the brain from harmful substances.
This oxidative damage impairs the ability of oligodendrocytes to repair myelin, a process known as remyelination. Without effective remyelination, nerve fibers remain exposed and vulnerable, leading to the progressive neurological decline seen in MS. Furthermore, iron overload can trigger a specific type of cell death called ferroptosis, which is driven by lipid peroxidation—a process where ROS attack the lipids in cell membranes. Ferroptosis accelerates the loss of myelin and nerve cells, worsening the disease.
Oxidative stress also influences the immune system’s behavior in MS. Immune cells like macrophages and microglia, which are involved in inflammation and tissue repair, can accumulate iron in MS lesions. This iron accumulation pushes these cells toward a pro-inflammatory state, increasing neuroinflammation and further oxidative damage. On the other hand, iron deficiency can impair the function of T and B lymphocytes, key players in immune regulation, potentially exacerbating the autoimmune attack on myelin.
Another aspect of oxidative stress in MS is related to mitochondrial dysfunction. Mitochondria, the energy-producing organelles in cells, are both sources and targets of ROS. In MS, mitochondrial damage caused by oxidative stress leads to reduced energy production and increased ROS generation, creating a vicious cycle that contributes to nerve cell injury and death. This mitochondrial impairment is thought to underlie some of the chronic neurodegeneration and disability progression in MS.
The concept of “virtual hypoxia” has been proposed to describe how oxidative stress and inflammation create a state similar to oxygen deprivation in brain tissue, even when oxygen supply is adequate. Activated microglia and macrophages produce ROS and inflammatory molecules that disrupt cellular metabolism, leading to energy failure and further oxidative damage. This virtual hypoxia contributes to the chronic progression of MS, especially in its progressive forms.
Oxidative stress also activates various inflammatory signaling pathways, which amplify immune responses and tissue damage. Excess ROS can trigger the release of pro-inflammatory cytokines and chemokines, molecules that recruit and activate more immune cells, perpetuating inflammation. This ongoing inflammation damages myelin and nerve cells, creating a feedback loop where oxidative stress and immune activation feed into each other.
In addition to damaging cells directly, oxidative stress affects the integrity of the blood-brain barrie
