Iron Chelation and Multiple Sclerosis

Abstract

Histochemical and MRI studies have demonstrated that MS (multiple sclerosis) patients have abnormal deposition of iron in both gray and white matter structures. Data is emerging indicating that this iron could partake in pathogenesis by various mechanisms, e.g., promoting the production of reactive oxygen species and enhancing the production of proinflammatory cytokines. Iron chelation therapy could be a viable strategy to block iron-related pathological events or it can confer cellular protection by stabilizing hypoxia inducible factor 1α, a transcription factor that normally responds to hypoxic conditions. Iron chelation has been shown to protect against disease progression and/or limit iron accumulation in some neurological disorders or their experimental models. Data from studies that administered a chelator to animals with experimental autoimmune encephalomyelitis, a model of MS, support the rationale for examining this treatment approach in MS. Preliminary clinical studies have been performed in MS patients using deferoxamine. Although some side effects were observed, the large majority of patients were able to tolerate the arduous administration regimen, i.e., 6–8 h of subcutaneous infusion, and all side effects resolved upon discontinuation of treatment. Importantly, these preliminary studies did not identify a disqualifying event for this experimental approach. More recently developed chelators, deferasirox and deferiprone, are more desirable for possible use in MS given their oral administration, and importantly, deferiprone can cross the blood–brain barrier. However, experiences from other conditions indicate that the potential for adverse events during chelation therapy necessitates close patient monitoring and a carefully considered administration regimen.

Solid microparticles based on chitosan or methyl-β-cyclodextrin: A first formulative approach to increase the nose-to-brain transport of deferoxamine mesylate

“…Data concerning animal and human studies show that DFO has diverse neuroprotective effects and its use is beneficial in Huntington’s [5,6], Alzheimer’s [7,8], Parkinson’s [9–11] disease, amyotrophic lateral sclerosis [12], prionopathies [13], neuroferritinopathy [14], intracerebral hemorrhage [3,15], ischemic stroke [16,17], multiple sclerosis [18], and spinal cord injury [19]. Unfortunately, most of these studies used forms of systemic administration or intracranial injections that are not suitable for human use [9].…”

Dynamics of brain iron levels in multiple sclerosis

“…5 In addition, perivascular inflammation may damage vessel walls, leading to blood extravasation with subsequent perivascular iron deposition. [29][30][31][32] While iron thus accumulates within the basal ganglia, the opposite occurs within the thalamus. We found a decrease of R2* relaxation rates during follow-up in CIS and even more pronounced in MS.…”

“…Histochemical studies revealed iron deposits around MS plaques, 11,27,28 indicating that iron could originate from damaged brain structures. One may further speculate that iron is subsequently redistributed within the brain, 29,30 where in particular deep gray matter structures could serve as a sink. 5 In addition, perivascular inflammation may damage vessel walls, leading to blood extravasation with subsequent perivascular iron deposition.…”

Iron chelation in the treatment of neurodegenerative diseases

“…Several studies showed that chelators ameliorate experimental autoimmune encephalomyelitis which is an animal model of MS. These promising results triggered interest in examining iron removal therapy in MS patients [169][170][171].…”