Manganese-based superoxide dismutase mimics modify both acute and long-term outcome severity in a Drosophila melanogaster model of classic galactosemia.

Abstract

AIMS:

The goal of this study was to use two manganese (Mn)-based superoxide dismutase (SOD) mimics to test the hypothesis that reactive oxygen species contribute to both acute and long-term outcomes in a galactose-1P uridylyltransferase (GALT)-null Drosophila melanogaster model of classic galactosemia.

RESULTS:

We tested the impact of each of two Mn porphyrin SOD mimics, MnTnBuOE-2-PyP(5+), and MnTE-2-PyP(5+), (i) on survival of GALT-null Drosophila larvae reared in the presence versus absence of dietary galactose and (ii) on the severity of a long-term movement defect in GALT-null adult flies. Both SOD mimics conferred a significant survival benefit to GALT-null larvae exposed to galactose but not to controls or to GALT-null larvae reared in the absence of galactose. One mimic, MnTE-2-PyP(5+), also largely rescued a galactose-independent long-term movement defect otherwise seen in adult GALT-null flies. The survival benefit of both SOD mimics occurred despite continued accumulation of elevated galactose-1P in the treated animals, and studies of thiolated proteins demonstrated that in both the presence and absence of dietary galactose MnTE-2-PyP(5+) largely prevented the elevated protein oxidative damage otherwise seen in GALT-null animals relative to controls.

INNOVATION AND CONCLUSIONS:

Our results confirm oxidative stress as a mediator of acute galactose sensitivity in GALT-null Drosophila larvae and demonstrate for the first time that oxidative stress may also contribute to galactose-independent adult outcomes in GALT deficiency. Finally, our results demonstrate for the first time that both MnTnBuOE-2-PyP(5+) and MnTE-2-PyP(5+) are bioavailable and effective when administered through an oral route in a D. melanogaster model of classic galactosemia.

• Authors: Patricia P Jumbo-Lucioni, Emily L Ryan, Marquise L Hopson, Heather M Bishop, Tin Weitner, Artak Tovmasyan, Ivan Spasojevic, Ines Batinic-Haberle, Yongliang Liang, Dean P Jones, Judith L Fridovich-Keil
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 20 Issue 15 Pg. 2361-71 (May 20 2014) ISSN: 1557-7716 [Electronic] United States
• PMID: 23758052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Metalloporphyrins
• Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin
• Reactive Oxygen Species
• Superoxide Dismutase
• Glutathione
• Cysteine
• Galactose

Topics

• Animals
• Cysteine (blood, metabolism)
• Disease Models, Animal
• Drosophila melanogaster
• Galactose (metabolism)
• Galactosemias (drug therapy, genetics, metabolism, mortality)
• Glutathione (blood, metabolism)
• Male
• Metabolic Networks and Pathways
• Metalloporphyrins (pharmacokinetics, pharmacology)
• Molecular Mimicry
• Oxidation-Reduction (drug effects)
• Reactive Oxygen Species (metabolism)
• Superoxide Dismutase (chemistry, metabolism, pharmacology)