X-linked glucose-6-phosphate dehydrogenase deficiency inMus musculus

Pretsch, Walter; Charles, Daniel J.; Merkle, Siegbert

doi:10.1007/bf00555491

Cited by 61 publications

(48 citation statements)

References 23 publications

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“…Female and male mutant G6PD-deficient mice 16 (Medical Research Council, U.K.), 20−30 g, 1.5−2.0 years of age, were housed four per plastic cage with ground corn cob bedding (Beta Chip, Northeastern Products Corp.). The basis of the mutation is an ethylnitrosourea-induced A−T transversion mutation in the exon 1 of the G6PD gene, which is believed to cause a splicing error during posttranslational processing.…”

Section: ■ Methodsmentioning

confidence: 99%

“…15 The deficiency in this strain results from a decrease in total G6PD protein expression causing an overall reduction in activity. 16 The results suggest that G6PD may be an essential protective enzyme preventing ROS-initiated neurodegenerative oxidative damage associated with aging. Since G6PD deficiencies are the most common human enzymopathy, 1 the mutant G6PD-deficient mouse may provide important insights into previously unappreciated risk factors for some neurodegenerative diseases.…”

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confidence: 96%

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Brain Glucose-6-phosphate Dehydrogenase Protects against Endogenous Oxidative DNA Damage and Neurodegeneration in Aged Mice

Jeng

Loniewska

Wells

2013

ACS Chem. Neurosci.

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Glucose-6-phosphate dehydrogenase (G6PD) protects the embryo from endogenous and xenobiotic-enhanced oxidative DNA damage and embryopathies. Here we show in aged mice that G6PD similarly protects against endogenous reactive oxygen species (ROS)-mediated neurodegeneration. In G6PD-normal (G6PD +/+ ) and heterozygous (G6PD +/def ) and homozygous (G6PD def/def ) G6PD-deficient male and female mice at about 2 years of age, oxidative DNA damage in various brain regions was assessed by 8-oxo-2′-deoxyguanosine formation using high-performance liquid chromatography and immunohistochemistry. Morphological changes in brain sections were assessed by H&E staining. DNA oxidation was increased in G6PD def/def mice in the cortex (p < 0.02), hippocampus (p < 0.01) and cerebellum (p < 0.006) compared to G6PD +/+ mice, and was localized to distinct cell types. Histologically, in G6PD +/def mice, enhanced regionally and cellularly specific neurodegenerative changes were observed in those brain regions exhibiting elevated DNA oxidation, with a 53% reduction in the Purkinje cell count. These results show G6PD is important in protecting against the neurodegenerative effects of endogenous ROS in aging, and suggest that common hereditary G6PD deficiencies may constitute a risk factor for some neurodegenerative diseases.

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Section: ■ Methodsmentioning

confidence: 99%

mentioning

confidence: 96%

Brain Glucose-6-phosphate Dehydrogenase Protects against Endogenous Oxidative DNA Damage and Neurodegeneration in Aged Mice

Jeng

Loniewska

Wells

2013

ACS Chem. Neurosci.

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“…G6PD-deficient mice (G6PD def ) 13 were rederived in our laboratories from frozen embryos. G6PD def mice carry a mutation at the 5Ј untranslated sequence of the X-linked G6PD gene and, through a splicing defect, exhibit decreased G6PD protein expression and enzyme activity.…”

Section: G6pd-deficient Animalsmentioning

confidence: 99%

Increased Myocardial Dysfunction After Ischemia-Reperfusion in Mice Lacking Glucose-6-Phosphate Dehydrogenase

et al. 2004

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Background-Free radical injury contributes to cardiac dysfunction during ischemia-reperfusion. Detoxification of free radicals requires maintenance of reduced glutathione (GSH) by NADPH. The principal mechanism responsible for generating NADPH and maintaining GSH during periods of myocardial ischemia-reperfusion remains unknown. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, generates NADPH in a reaction linked to the de novo production of ribose. We therefore hypothesized that G6PD is essential for maintaining GSH levels and protecting the heart during ischemia-reperfusion injury. Methods and Results-Susceptibility to myocardial ischemia-reperfusion injury was determined in Langendorff-perfused hearts isolated from wild-type mice (WT) and mice lacking G6PD (G6PD def ) (20% of WT myocardial G6PD activity). During global zero-flow ischemia, cardiac function was similar between WT and G6PD def hearts. On reperfusion, however, cardiac relaxation and contractile performance were greatly impaired in G6PD def myocardium, as demonstrated by elevated end-diastolic pressures and decreased percent recovery of developed pressure relative to WT hearts. Contractile dysfunction in G6PD def hearts was associated with depletion of total glutathione stores and impaired generation of GSH from its oxidized form. Increased ischemia-reperfusion injury in G6PD def hearts was reversed by treatment with the antioxidant MnTMPyP but unaffected by supplementation of ribose stores.Conclusions-These results demonstrate that G6PD is an essential myocardial antioxidant enzyme, required for maintaining cellular glutathione levels and protecting against oxidative stress-induced cardiac dysfunction during ischemia-reperfusion.

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“…In this study, we tested whether a G6PDD mouse model, [11][12][13][14] with a moderated degree of G6PD deficiency (10-15% of normal enzyme activity) is similar to that seen in the most common African type A-G6PDD phenotype in humans, and could be used to predict primaquine-induced hemolysis.…”

Section: Introductionmentioning

confidence: 99%

An In vivo Drug Screening Model Using Glucose-6-Phosphate Dehydrogenase Deficient Mice to Predict the Hemolytic Toxicity of 8-Aminoquinolines

Zhang

Gao

Ishida

et al. 2013

The American Society of Tropical Medicine and Hygiene

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Abstract. Anti-malarial 8-aminoquinolines drugs cause acute hemolytic anemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDD). Efforts to develop non-hemolytic 8-aminoquinolines have been severely limited caused by the lack of a predictive in vivo animal model of hemolytic potential that would allow screening of candidate compounds. This report describes a G6PDD mouse model with a phenotype closely resembling the G6PDD phenotype found in the African A-type G6PDD human. These G6PDD mice, given different doses of primaquine, which used as a reference hemolytic drug, display a full array of hemolytic anemia parameters, consistently and reproducibly. The hemolytic and therapeutic indexes were generated for evaluation of hemotoxicity of drugs. This model demonstrated a complete hemolytic toxicity response to another known hemolytic antimalarial drug, pamaquine, but no response to non-hemolytic drugs, chloroquine and mefloquine. These results suggest that this model is suitable for evaluation of selected 8-AQ type candidate antimalarial drugs for their hemolytic potential.

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X-linked glucose-6-phosphate dehydrogenase deficiency inMus musculus

Cited by 61 publications

References 23 publications

Brain Glucose-6-phosphate Dehydrogenase Protects against Endogenous Oxidative DNA Damage and Neurodegeneration in Aged Mice

Brain Glucose-6-phosphate Dehydrogenase Protects against Endogenous Oxidative DNA Damage and Neurodegeneration in Aged Mice

Increased Myocardial Dysfunction After Ischemia-Reperfusion in Mice Lacking Glucose-6-Phosphate Dehydrogenase

An In vivo Drug Screening Model Using Glucose-6-Phosphate Dehydrogenase Deficient Mice to Predict the Hemolytic Toxicity of 8-Aminoquinolines

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