Affiliations: [a] Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA | [b] Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA | [c] Department of Ophthalmology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
Correspondence:
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Correspondence to: Peter F. Kador, PhD, FARVO, College of Pharmacy, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA. Tel.: +1 402 559 9261; Fax: +1 402 559 9543; E-mail: pkador@unmc.edu.
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. Conclusion:These studies demonstrate that these MFAOs have metal attenuating properties with therapeutic potential in the treatment of both AMD and AD.
