Abstract
Many studies have established a role for oxidative stress and mitochondrial dysfunction as an important mechanism in the pathogenesis of neuronal disorders. Metalloporphyrins are a class of catalytic antioxidants that are capable of detoxifying a wide range of reactive oxygen species. The AEOL112 series of glyoxylate metalloporphyrins were designed with increased lipid solubility for better oral bioavailability and penetration of the blood-brain barrier. The goal of this study was to develop an in vitro assay using rat brain mitochondria to reliably detect endogenously released hydrogen peroxide (H2O2) and identify glyoxylate metalloporphyrins based on rank order of potency for removal of physiologically relevant H2O2. A polarographic method was established for the sensitive, accurate, and reproducible detection of low levels of H2O2. The assay identified several potent glyoxylate metalloporphyrins with H2O2 scavenging potencies (IC50) in the nanomolar range. These results provide a simplified in vitro model system to detect physiologically generated mitochondrial H2O2 as a screening tool to predict the biological efficacy of potential therapeutic entities.
Footnotes
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This work was supported by NINDS, National Institutes of Health Grants RO1NS045748, R01NS039587, and R21NS053548 (to M.P.) and Aeolus Pharmaceuticals (to M.P. and B.J.D.).
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B.J.D. is a consultant for and holds equity in Aeolus Pharmaceuticals, which is developing catalytic antioxidants as therapeutic agents.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.132134.
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ABBREVIATIONS: ROS, reactive oxygen species; MnTBAP, manganese (III) meso-tetrakis (4-carboxyphenyl or benzoic acid) porphyrin; AEOL10150, manganese (III) meso-tetrakis (N,N′-diethylimidazolium-2-yl) porphyrin; AEOL10113, manganese (III) meso-tetrakis (N-ethyl pyridinium-2-yl) porphyrin; PQ2+, paraquat; LDH, lactate dehydrogenase; COX, cytochrome c oxidase; DMSO, dimethyl sulfoxide; HRP, horseradish peroxidase; SOD, superoxide dismutase; TBA, thiobarbituric acid; TBARS, thiobarbituric acid reactive species; MDA, malondialdehyde; MnTE-2-PyP, manganese tetrakis-(N-ethyl-2-pyridyl) porphyrin.
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↵1 Current affiliation: Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, Colorado.
- Received September 27, 2007.
- Accepted December 5, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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Inhibition of Mitochondrial Hydrogen Peroxide Production by Lipophilic Metalloporphyrins
