Molecular shuttle chelation

The use of ascorbate, desferrioxamine and Feralex-G in combination to remove nuclear bound aluminum

Theo P. Kruck, Jian Guo Cui, Maire E. Percy, Walter J. Lukiw

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

1. Abundant data suggest that aluminum (Al(III)) exposure may be an environmental risk factor contributing to the development, progression and/or neuropathology of several human neurodegenerative disorders, including Alzheimer's disease (AD). 2. Nuclei appear to be one directed target for Al(III) binding, accumulation, and Al(III)-mediated dysfunction due in part to their high content of polyphosphorylated nucleic acids, nucleotides, and nucleoproteins. 3. The design of chelation therapies dealing with the removal of Al(III) from these genetic compartments therefore represents an attractive strategy to alleviate the development and/or progression of central nervous system dysfunction that may arise from excessive Al(III) exposure. 4. In this study we have investigated the potential application of 10 natural and synthetic Al(III) chelators, including ascorbate (AS), desferrioxamine (DF), and Feralex-G (FG), used either alone or in combination, to remove Al(III) preincubated with intact human brain cell nuclei. 5. Although nuclear bound Al(III) was found to be highly refractory to removal, the combination of AS+FG was found to be particularly effective in removing Al(III) from the nuclear matrix. 6. Our data suggest that chelators carrying cis-hydroxy ketone groups, such as FG, are particularly suited to the removal of Al(III) from complex biological systems. 7. We further suggest a mechanism whereby small chelating molecules may penetrate the nucleus, bind Al(III). diffuse to regions accessible by the larger DF or FG molecules and transfer their Al(III) to DF or FG. 8. The proposed mechanism, called molecular shuttle chelation may provide a useful pharmacotherapy in the potential treatment of Al(III) overload disease.

Original languageEnglish
Pages (from-to)443-459
Number of pages17
JournalCellular and Molecular Neurobiology
Volume24
Issue number3
DOIs
StatePublished - Jun 1 2004

Fingerprint

Deferoxamine
Chelation
Aluminum
Chelating Agents
Chelation Therapy
Drug therapy
Nuclear Matrix
Molecules
Nucleoproteins
Neurology
Biological systems
Ketones
Cell Nucleus
Neurodegenerative Diseases
Refractory materials
Nucleic Acids
Brain
Alzheimer Disease
Nucleotides
Central Nervous System

Keywords

  • Aluminum [Al(III)]
  • Alzheimer's disease
  • Amyotrophic lateral sclerosis
  • Ascorbate
  • Chelation therapy
  • Desferrioxamine
  • Feralex-G
  • Glucose transporter
  • molecular shuttle chelation
  • Nuclei
  • Vitamin C

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Biochemistry
  • Cell Biology
  • Genetics

Cite this

Molecular shuttle chelation : The use of ascorbate, desferrioxamine and Feralex-G in combination to remove nuclear bound aluminum. / Kruck, Theo P.; Cui, Jian Guo; Percy, Maire E.; Lukiw, Walter J.

In: Cellular and Molecular Neurobiology, Vol. 24, No. 3, 01.06.2004, p. 443-459.

Research output: Contribution to journalArticle

Kruck, Theo P. ; Cui, Jian Guo ; Percy, Maire E. ; Lukiw, Walter J. / Molecular shuttle chelation : The use of ascorbate, desferrioxamine and Feralex-G in combination to remove nuclear bound aluminum. In: Cellular and Molecular Neurobiology. 2004 ; Vol. 24, No. 3. pp. 443-459.
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