Multiple sclerosis (MS) is a complex neurodegenerative disease characterized by immune-mediated damage to the central nervous system, leading to demyelination, neuroinflammation, and progressive neurological decline. Among the many factors implicated in MS progression, abnormal iron metabolism and accumulation in the brain have attracted considerable attention. This has led to the exploration of **chelation and iron-handling therapies** as potential strategies to alter neurodegeneration in MS.
Iron is essential for normal brain function, involved in processes such as myelin synthesis, mitochondrial respiration, and neurotransmitter production. However, excess iron, especially in a free or poorly bound form, can catalyze the production of reactive oxygen species (ROS) through Fenton chemistry, leading to oxidative stress, lipid peroxidation, and ultimately cell death. This oxidative damage is a key contributor to neurodegeneration in MS. Iron accumulation has been observed in MS lesions and in deep gray matter structures, correlating with disease severity and progression.
**Chelation therapy** involves the use of agents that bind excess iron, facilitating its removal or redistribution to reduce its toxic effects. The rationale behind chelation in MS is to mitigate iron-induced oxidative stress and inflammation, thereby protecting neurons and oligodendrocytes from ferroptosis—a form of iron-dependent programmed cell death increasingly recognized in neurodegenerative diseases including MS. Ferroptosis involves iron-mediated lipid peroxidation damaging cell membranes, and targeting this pathway offers a novel therapeutic angle.
Several iron chelators, such as deferoxamine, deferiprone, and deferasirox, have been studied in neurodegenerative contexts. These agents differ in their ability to cross the blood-brain barrier, their iron-binding affinities, and side effect profiles. In MS, preclinical studies suggest that chelators can reduce iron accumulation, decrease oxidative damage, and improve neurological outcomes in animal models. For example, chelation has been shown to reduce microglial activation and neuroinflammation, which are central to MS pathology.
Beyond direct chelation, therapies that modulate iron metabolism proteins—such as ferritin, transferrin, and ferroportin—are also under investigation. These proteins regulate iron storage, transport, and export, and their dysregulation contributes to iron overload in MS lesions. By restoring normal iron homeostasis, these approaches aim to prevent iron-induced neuronal injury.
However, the application of chelation therapy in MS faces several challenges. Iron is vital for many physiological functions, so indiscriminate removal can cause systemic iron deficiency and anemia. Therefore, chelation must be carefully balanced to reduce harmful iron accumulation without impairing essential iron-dependent processes. Additionally, the timing of therapy is critical; early intervention may prevent irreversible damage, while late-stage chelation might have limited benefit.
Clinical trials of iron chelators in MS are limited but emerging. Some studies report modest improvements in MRI markers of iron load and neuroinflammation, while others highlight the need for better-targeted chelators with improved brain penetration and safety profiles. Combination therapies that include antioxidants, anti-inflammatory agents, and iron modulators may enhance efficacy by addressing multiple pathological mechanisms simultaneously.
In parallel, non-chelation iron-handling strategies are being explored. These include antioxidants that neutralize ROS generated by iron, dietary interventions to modulate systemic iron levels, and drugs targeting ferroptosis pathways to inhibit iron-dependent cell death. Such approaches may complement chelation by protecting vulnerable brain cells from iron-induced oxidative damage.
In summary, **chelation and iron-handling therapies represent promising but still experimental avenues to alter neurodegeneration in MS**. They target a fundamental pathological process—iron-mediated oxidative stress and ferroptosis—that contributes to neuronal and oligodendrocyte loss. While preclinical data are encouraging, more research is needed to optimize these therapies, determine appropriate patient populations, an
