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Hiroyoshi Kawada, Peter Kador; MULTIFUNCTIONAL ANTIOXIDANTS PROTECT CELLS FROM MITOCHONDRIAL DYSFUNCTION AND ABETA NEUROTOXICITY. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2176.
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© ARVO (1962-2015); The Authors (2016-present)
We have synthesized orally active multifunctional antioxidants (MFAOs) possessing distinct free radical scavenging activity and independent metal attenuating activity and demonstrated in rats that they delay cataract formation and protect the photoreceptor layer against light damage. Since mitochondrial dysfunction and amyloid beta (Aβ) neurotoxicity are associated with age-related retinal changes, the effect of MFAOs on these factors have been investigated.
Human neuroblastoma (SH-SY5Y) cells and retinal pigmented epithelial (RPE) cells were pre-incubated with medium containing 1 mM/10 µM of select MFAOs along with their respective nonfunctional parent compounds as controls, and clioquinol (CQ). Mitochondrial viability was assessed after 3-hr exposure to manganese chloride with/without the presence of drugs using Hoechst 33342 and rhodamine 123 staining. The neurotoxic potential of Zn promoted Aβ aggregation on these cells was evaluated with Zinquin staining (10 µM) which visualizes the cellular levels of labile Zn released from the Aβ:Zn complex by MFAOs, their respective nonfunctional parent compounds or CQ. Cellular fluorescence was evaluated using Zeiss confocal scanning laser microscopy (LSM).
The mitochondria of cells stained with rhodamine fluoresce and exposure to manganese chloride induces mitochondrial dysfunction which results in loss of fluorescent staining. Cells treated with MFAOs or CQ in the presence of manganese chloride retained fluorescence while fluorescence was lost when the cells were treated with the nonfunctional parent compounds. Zinquin staining of cells exposed to Aβ:Zn aggregates and MFAOs or CQ demonstrated the presence of labile Zn suggesting that these compounds have a metal attenuating effect on the Aβ:Zn aggregate. Similar Zinquin staining was not observed in cells similarly exposed to the Aβ:Zn aggregates and treated with the nonfunctional parent compounds.
MFAOs protect both human neuroblastoma and RPE cells against manganese chloride induced mitochondrial dysfunction and neurotoxicity of Zn promoted Aβ aggregation by releasing Zn from the Zn-Aβ complex. Since mitochondrial dysfunction and Zn-Aβ complex are both present in age-related macular degeneration, MFAOs may have therapeutic potential.
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