Abstract
Iron chelation has been introduced as a new therapeutic concept for the treatment of neurodegenerative diseases with features of iron overload. At difference with iron chelators used in systemic diseases, effective chelators for the treatment of neurodegenerative diseases must cross the blood–brain barrier. Given the promissory but still inconclusive results obtained in clinical trials of iron chelation therapy, it is reasonable to postulate that new compounds with properties that extend beyond chelation should significantly improve these results. Desirable properties of a new generation of chelators include mitochondrial destination, the center of iron-reactive oxygen species interaction, and the ability to quench free radicals produced by the Fenton reaction. In addition, these chelators should have moderate iron binding affinity, sufficient to chelate excessive increments of the labile iron pool, estimated in the micromolar range, but not high enough to disrupt physiological iron homeostasis. Moreover, candidate chelators should have selectivity for the targeted neuronal type, to lessen unwanted secondary effects during long-term treatment. Here, on the basis of a number of clinical trials, we discuss critically the current situation of iron chelation therapy for the treatment of neurodegenerative diseases with an iron accumulation component. The list includes Parkinson’s disease, Friedreich’s ataxia, pantothenate kinase-associated neurodegeneration, Huntington disease and Alzheimer’s disease. We also review the upsurge of new multifunctional iron chelators that in the future may replace the conventional types as therapeutic agents for the treatment of neurodegenerative diseases.
Highlights
Iron content increases with age in several regions of the brain
A wide variety of neurological diseases are characterized by the accumulation of iron in different areas of the central nervous system; these diseases include Parkinson’s disease (PD) and other parkinsonisms such as Lewy bodies dementia, progressive supranuclear palsy, corticobasal degeneration [16,17,18,19,20,21], the Westfal variant of Huntington disease [22], Alzheimer’s disease (AD) [23,24,25,26,27], Friedreich’s ataxia [28], pantothenate kinase-associated neurodegeneration [29,30,31] and other neuropathologies associated with brain iron accumulation [32,33,34]
Since astrocytes display preferential transport and metabolism of glucose compared to neurons [201], it would be expected that metal-hexose multifunctional agents (MFAs) should preferentially accumulate in astrocytes
Summary
Iron content increases with age in several regions of the brain. high levels of non-heme iron are found in the globus pallidus, the red nucleus, substantia nigra, cortex and putamen; in contrast, the iron content of the medulla oblongata does not change with age whereas the iron content of the thalamus decreases from age 30 to 90 [1,2,3]. The causes underlying the increase in brain iron with age remain elusive. It is unclear whether this increase is a reflection of total body iron, since a report shows that non-heme iron in the liver does not change with age [1], body stores of iron, as determined by circulating ferritin levels, seem to increase with age [4]. Abundant evidence suggests that disturbed iron homeostasis and mitochondrial dysfunction play important roles in the development of an increasing number of neurodegenerative diseases [3,5,6,7,8,9]. A review on the current evidence of the benefits and drawbacks of iron chelation therapy, and the analysis of new compounds that could be used for the treatment of neurodegenerative diseases, follows
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
