title: Effects of multifunctional antioxidants on mitochondrial dysfunction and amyloid-β metal dyshomeostasis.
abstract: BACKGROUND
  Redox-active metal dyshomeostasis and oxidative stress are associated with mitochondrial dysfunction and amyloid-β (Aβ) neurotoxicity that are linked to both the development of age-related macular degeneration (AMD) and Alzheimer's disease (AD). As potential therapeutic agents, orally active multifunctional antioxidants (MFAOs) possessing two independent functional groups capable of binding redox-active metals and scavenging free radicals have been synthesized.
  
  
  OBJECTIVE
  To determine whether MFAOs affect mitochondrial function and reduce the presence of Aβ plaque formation.
  
  
  METHODS
  The MFAOs were evaluated in cultured SH-SY5Y cells and ARPE-19 cells. MFAO effects on mitochondrial function were investigated using rhodamine 123 staining after 2 hour exposure to MnCl2. MFAO effects on Aβ:Zn complex formation were evaluated with Zinquin staining and the ability of the Aβ:Zn complex to be degraded by matrix metalloproteinase-2 (MMP-2). The ability of MFAOs to reduce Aβ plaque in the brain was determined by orally feeding MFAO for one year to B6;129-Psen1tm1Mpm Tg(AβPPSwe,tauP301L) 1Lfa/Mmjax transgenic mice. Aβ levels were determined by ELISA.
  
  
  RESULTS
  MFAOs neither adversely affected mitochondrial signaling nor labile cytoplasmic zinc levels. MFAOs protected cells against Mn2+-induced mitochondrial dysfunction. MFAOs also removed zinc from the Aβ:Zn complex so that Aβ plaque could be degraded by MMP-2. Zinquin staining indicated that the removed zinc was present in the cytoplasm as labile zinc. Orally administered MFAOs reduced the brain levels of both Aβ40 and Aβ42 isoforms of Aβ.
  
  
  CONCLUSIONS
  These studies demonstrate that these MFAOs have metal attenuating properties with therapeutic potential in the treatment of both AMD and AD.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Kawada
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Blessing
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kiyota
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Theodor
authors.initials: T
authors.lastname: Woolman
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Winchester
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA Department of Ophthalmology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Kador
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects; D005456:Fluorescent Dyes; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D015363:Quinolones; D020112:Rhodamine 123; D014105:Tosyl Compounds; D015032:Zinc / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D005456:Fluorescent Dyes; D015363:Quinolones; D014105:Tosyl Compounds; D020112:Rhodamine 123; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D015032:Zinc; C084731:zinquin
keywords: Age-related macular degeneration; Alzheimer's disease; JAX transgenic Alzheimer mouse; amyloid-β; clioquinol; mitochondrial dysfunction; multifunctional antioxidants