8-hydroxy-2--deoxyguanosine and Huntington-Disease

To evaluate plasma 8-hydroxy-deoxy-guanosine (8OHdG) levels as a potential biomarker of premanifest and early Huntington disease (HD).. Personnel from 2 independent laboratories quantified 8OHdG in blinded longitudinal plasma samples taken 24 months apart from 160 TRACK-HD participants, as well as samples containing control plasma with added ("spiked") 8OHdG. One laboratory used a liquid chromatography-electrochemical array (LCECA) assay, and the other used liquid chromatography-mass spectrometry (LCMS).. The LCMS assay was more accurate than the LCECA assay for measurements of "spiked" 8OHdG levels in plasma. Neither assay demonstrated cross-sectional differences in plasma 8OHdG among controls, premanifest HD, and early symptomatic HD. Similarly, neither assay showed longitudinal changes in any disease group over 24 months.. Plasma concentration of 8OHdG is not a biomarker of disease state or progression in HD. We recommend that future putative biomarker studies use blinded sample analysis, standard curves, independent analytical methods, and strict quality control of sample collection and storage.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Deoxyguanosine; Disease Progression; Female; Humans; Huntington Disease; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Single-Blind Method

We analyzed plasma 8OHdG concentrations in 20 individuals enrolled in the Pre-2CARE study before and after treatment with CoQ. Treatment resulted in a mean reduction in 8OHdG of 2.9 ± 2.9 pg/ml for the cohort (p = 0.0003) and 3.0 ± 2.6 pg/ml, for the HD group (p = 0.002). Baseline 8OHdG levels were not different between individuals with HD and controls (19.3 ± 3.2 pg/ml vs. 19.5 ± 4.7 pg/ml, p = 0.87) though baseline CoQ levels were elevated in HD compared with controls (p < 0.001). CoQ treatment reduces plasma 8OHdG and this reduction may serve as a marker of pharmacologic activity of CoQ in HD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Case-Control Studies; Deoxyguanosine; Female; Humans; Huntington Disease; Male; Middle Aged; Oxidative Stress; Ubiquinone; Young Adult

In a randomized, double-blind, placebo-controlled study in 64 subjects with Huntington disease (HD), 8 g/day of creatine administered for 16 weeks was well tolerated and safe. Serum and brain creatine concentrations increased in the creatine-treated group and returned to baseline after washout. Serum 8-hydroxy-2'-deoxyguanosine (8OH2'dG) levels, an indicator of oxidative injury to DNA, were markedly elevated in HD and reduced by creatine treatment.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biological Availability; Biomarkers; Brain; Creatine; Deoxyguanosine; Double-Blind Method; Female; Humans; Huntington Disease; Male; Middle Aged

Huntington's disease (HD) is a monogenic, progressive, neurodegenerative disorder with currently no available treatment. The Libechov transgenic minipig model for HD (TgHD) displays neuroanatomical similarities to humans and exhibits slow disease progression, and is therefore more powerful than available mouse models for the development of therapy. The phenotypic characterization of this model is still ongoing, and it is essential to validate biomarkers to monitor disease progression and intervention. In this study, the behavioral phenotype (cognitive, motor and behavior) of the TgHD model was assessed, along with biomarkers for mitochondrial capacity, oxidative stress, DNA integrity and DNA repair at different ages (24, 36 and 48 months), and compared with age-matched controls. The TgHD minipigs showed progressive accumulation of the mutant huntingtin (mHTT) fragment in brain tissue and exhibited locomotor functional decline at 48 months. Interestingly, this neuropathology progressed without any significant age-dependent changes in any of the other biomarkers assessed. Rather, we observed genotype-specific effects on mitochondrial DNA (mtDNA) damage, mtDNA copy number, 8-oxoguanine DNA glycosylase activity and global level of the epigenetic marker 5-methylcytosine that we believe is indicative of a metabolic alteration that manifests in progressive neuropathology. Peripheral blood mononuclear cells (PBMCs) were relatively spared in the TgHD minipig, probably due to the lack of detectable mHTT. Our data demonstrate that neuropathology in the TgHD model has an age of onset of 48 months, and that oxidative damage and electron transport chain impairment represent later states of the disease that are not optimal for assessing interventions.This article has an associated First Person interview with the first author of the paper.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Animals, Genetically Modified; Behavior, Animal; Deoxyguanosine; Disease Models, Animal; DNA Damage; DNA Repair; Energy Metabolism; Genome; Humans; Huntingtin Protein; Huntington Disease; Mitochondria; Nerve Degeneration; Organ Specificity; Swine; Swine, Miniature

Peripheral oxidative biomarkers could be useful for monitoring clinical features of Huntington's disease (HD).. Cu/Zn-superoxide dismutase (Cu/Zn-SOD), neuron-specific enolase (NSE) and 8-hydroxy-2'-deoxyguanosine (8-oxoGua) serum levels were analysed in 18 HD patients and 10 controls. Clinical measures were recorded from each HD patients.. Cu/Zn-SOD, NSE and 8-oxoGua values were higher in HD patients than in controls. Cu/Zn-SOD and NSE correlated positively. No correlation was observed between the biomarkers analysed and the clinical measures assessed.. Serum oxidative biomarkers could express the neuronal oxidative processes going on in HD patients but are inadequate to evaluate clinical features of the disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Case-Control Studies; Deoxyguanosine; Female; Humans; Huntington Disease; Male; Middle Aged; Oxidative Stress; Phosphopyruvate Hydratase; Superoxide Dismutase

Leukocyte 8-hydroxydeoxyguanosine (8OHdG) is an indicator of oxidative stress, impaired metabolism, and mitochondrial dysfunction, features that have been implicated in Huntington disease (HD). Increased levels of 8OHdG have been reported in the caudate, parietal cortex, and peripherally in the serum and leukocytes, in patients diagnosed with HD. However, little is known about levels in prodromal patients and changes that might occur as the disease progresses. To address these issues, 8OHdG was tracked over time for a subset of participants enrolled in the PREDICT-HD study. Participants were stratified into four groups based on proximity to HD diagnosis at study entry: Controls (gene-negative individuals), Low (low probability of near-future diagnosis), Medium, and High. Blood samples were analyzed using Liquid Chromatography Electrochemical Array, and for comparison purposes, a separate cross-sectional sample was analyzed using liquid chromatography coupled with multiple-reaction-monitoring mass spectrometry. Longitudinal data analysis showed that initial status (at study entry) and annual rate of change varied as a function of proximity group, adjusting for sex, education, age at study entry, and site effects. Overall levels were lowest for the Control group and highest for the High group, and the rate of increase varied in a similar manner. The finding that 8OHdG concentrations increased as a function of proximity to projected disease diagnosis and duration indicates support for the continued assessment of 8OHdG as a robust clinical HD biomarker.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Blood Specimen Collection; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Deoxyguanosine; Disease Progression; Electrochemistry; Female; Humans; Huntington Disease; Leukocytes; Longitudinal Studies; Male; Mass Spectrometry; Middle Aged; Predictive Value of Tests

Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Deoxyguanosine; Humans; Huntington Disease

Coenzyme Q(10) (CoQ(10)) and creatine are promising agents for neuroprotection in neurodegenerative diseases via their effects on improving mitochondrial function and cellular bioenergetics and their properties as antioxidants. We examined whether a combination of CoQ(10) with creatine can exert additive neuroprotective effects in a MPTP mouse model of Parkinson's disease, a 3-NP rat model of Huntington's disease (HD) and the R6/2 transgenic mouse model of HD. The combination of the two agents produced additive neuroprotective effects against dopamine depletion in the striatum and loss of tyrosine hydroxylase neurons in the substantia nigra pars compacta (SNpc) following chronic subcutaneous administration of MPTP. The combination treatment resulted in significant reduction in lipid peroxidation and pathologic alpha-synuclein accumulation in the SNpc neurons of the MPTP-treated mice. We also observed additive neuroprotective effects in reducing striatal lesion volumes produced by chronic subcutaneous administration of 3-NP to rats. The combination treatment showed significant effects on blocking 3-NP-induced impairment of glutathione homeostasis and reducing lipid peroxidation and DNA oxidative damage in the striatum. Lastly, the combination of CoQ(10) and creatine produced additive neuroprotective effects on improving motor performance and extending survival in the transgenic R6/2 HD mice. These findings suggest that combination therapy using CoQ(10) and creatine may be useful in the treatment of neurodegenerative diseases such as Parkinson's disease and HD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 8-Hydroxy-2'-Deoxyguanosine; alpha-Synuclein; Analysis of Variance; Animals; Chromatography, High Pressure Liquid; Creatine; Deoxyguanosine; Disease Models, Animal; Dopamine; Drug Therapy, Combination; Glutathione; Glutathione Disulfide; Huntington Disease; Lipid Peroxidation; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Nitro Compounds; Parkinson Disease; Propionates; Rats; Rats, Inbred Lew; Tyrosine 3-Monooxygenase; Ubiquinone

Several human neurodegenerative disorders are characterized by the accumulation of 8-oxo-7,8-dihydroguanine (8-oxodG) in the DNA of affected neurons. This can occur either through direct oxidation of DNA guanine or via incorporation of the oxidized nucleotide during replication. Hydrolases that degrade oxidized purine nucleoside triphosphates normally minimize this incorporation. hMTH1 is the major human hydrolase. It degrades both 8-oxodGTP and 8-oxoGTP to the corresponding monophosphates. To investigate whether the incorporation of oxidized nucleic acid precursors contributes to neurodegeneration, we constructed a transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed. hMTH1 expression protected embryonic fibroblasts and mouse tissues against the effects of oxidants. Wild-type mice exposed to 3-nitropropionic acid develop neuropathological and behavioural symptoms that resemble those of Huntington's disease. hMTH1 transgene expression conferred a dramatic protection against these Huntington's disease-like symptoms, including weight loss, dystonia and gait abnormalities, striatal degeneration, and death. In a complementary approach, an in vitro genetic model for Huntington's disease was also used. hMTH1 expression protected progenitor striatal cells containing an expanded CAG repeat of the huntingtin gene from toxicity associated with expression of the mutant huntingtin. The findings implicate oxidized nucleic acid precursors in the neuropathological features of Huntington's disease and identify the utilization of oxidized nucleoside triphosphates by striatal cells as a significant contributor to the pathogenesis of this disorder.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Corpus Striatum; Deoxyguanosine; DNA Damage; DNA Repair Enzymes; DNA, Complementary; Embryo, Mammalian; Fibroblasts; Guanine; Humans; Huntingtin Protein; Huntington Disease; Mice; Mice, Transgenic; Nerve Tissue Proteins; Neurodegenerative Diseases; Nitro Compounds; Nuclear Proteins; Oxidation-Reduction; Oxidative Stress; Phosphoric Monoester Hydrolases; Propionates; Stem Cells

Increased oxidative stress and mitochondrial abnormalities contribute to neuronal dysfunction in Huntington's disease (HD). We investigated whether these pathological changes in HD brains may also be present in peripheral tissues. Leukocyte 8-hydroxydeoxyguanosine (8-OHdG) and plasma malondialdehyde (MDA) were elevated, and activities of erythrocyte Cu/Zn-superoxide dismutase (Cu/Zn-SOD) and glutathione peroxidase (GPx) reduced in 16 HD patients when compared to 36 age- and gender-matched controls. Deleted and total mitochondrial DNA (mtDNA) copy numbers were increased, whereas the mRNA expression levels of mtDNA-encoded mitochondrial enzymes are not elevated in HD leukocytes compared to the normal controls. Plasma MDA levels also significantly correlated with HD disease severity. These results indicate means to suppress oxidative damage or to restore mitochondrial functions may be beneficial to HD patients. Plasma MDA may be used as a potential biomarker to test treatment efficacy in the future, if confirmed in a larger, longitudinal study.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Biomarkers; Deoxyguanosine; DNA, Mitochondrial; Erythrocytes; Female; Humans; Huntington Disease; Male; Malondialdehyde; Middle Aged; Mitochondria; Oxidative Stress; Superoxide Dismutase

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10 (CoQ10). We have reported that CoQ10 is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ10 slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ10 from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ10 significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ10 resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ10 and CoQ9 were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ10 elevated CoQ10 plasma levels and significantly increased brain levels of CoQ9, CoQ10, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ10 exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ10 in HD patients are warranted.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adenosine Triphosphate; Animals; Body Weight; Coenzymes; Deoxyguanosine; Disease Models, Animal; Dose-Response Relationship, Drug; Huntingtin Protein; Huntington Disease; Male; Mice; Mice, Transgenic; Neostriatum; Nerve Tissue Proteins; Neuroprotective Agents; Nuclear Proteins; Rotarod Performance Test; Treatment Outcome; Ubiquinone

The effects of the peripheral benzodiazepine receptor (PBR) ligand, PK11195, were investigated in the rat striatum following the administration of quinolinic acid (QUIN). Intrastriatal QUIN injection caused an increase of PBR expression in the lesioned striatum as demonstrated by immunohistochemical analysis. Double immunofluorescent staining indicated PBR was primarily expressed in ED1-immunoreactive microglia but not in GFAP-immunoreactive astrocytes or NeuN-immunoreactive neurons. PK11195 treatment significantly reduced the level of microglial activation and the expression of pro-inflammatory cytokines and iNOS in QUIN-injected striatum. Oxidative-mediated striatal QUIN damage, characterized by increased expression of markers for lipid peroxidation (4-HNE) and oxidative DNA damage (8-OHdG), was significantly diminished by PK11195 administration. Furthermore, intrastriatal injection of PK11195 with QUIN significantly reduced striatal lesions induced by the excitatory amino acid and diminished QUIN-mediated caspase-3 activation in striatal neurons. These results suggest that inflammatory responses from activated microglia are damaging to striatal neurons and pharmacological targeting of PBR in microglia may be an effective strategy in protecting neurons in neurological disorders such as Huntington's disease.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antineoplastic Agents; Carrier Proteins; Caspases; Corpus Striatum; Cytokines; Deoxyguanosine; Disease Models, Animal; Ectodysplasins; Encephalitis; Gliosis; Huntington Disease; Isoquinolines; Ligands; Male; Membrane Proteins; Microglia; Nerve Degeneration; Neurotoxins; Nitric Oxide Synthase Type II; Oxidative Stress; Quinolinic Acid; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Tumor Necrosis Factors

Mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Huntington's disease (HD). We examined concentrations of 8-hydroxy-2-deoxyguanosine (OH(8)dG), a well-established marker of oxidative damage to DNA, in a transgenic mouse model of HD (R6/2). Increased concentrations of OH(8)dG were found in the urine, plasma and striatal microdialysates of the HD mice. Increased concentrations were also observed in isolated brain DNA at 12 and 14 weeks of age. Immunocytochemistry showed increased OH(8)dG staining in late stages of the illness. These results suggest that oxidative damage may play a role in the pathogenesis of neuronal degeneration in the R6/2 transgenic mouse model of HD.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Biomarkers; Brain; Cerebral Cortex; Corpus Striatum; Deoxyguanosine; DNA; DNA Damage; Female; Humans; Huntingtin Protein; Huntington Disease; Male; Mice; Mice, Transgenic; Microdialysis; Mitochondria; Models, Animal; Nerve Degeneration; Nerve Tissue Proteins; Nuclear Proteins; Oxidation-Reduction; Oxidative Stress

Oxidative damage to DNA may play a role in both normal aging and in neurodegenerative diseases. Using a sensitive high-performance liquid chromatography (HPLC) assay, we examined concentrations of 8-hydroxy-2-deoxyguanosine (OH8dG) in mitochondrial DNA (mtDNA) isolated from frontal and parietal cerebral cortex and from cerebellum in 22 Huntington's disease (HD) patients and 15 age-matched normal controls. A significant increase in OH8dG in mtDNA of parietal cortex was found in HD patients as compared with controls, while there were no significant changes in frontal cortex or cerebellum. The present findings are consistent with regionally specific oxidative damage in HD, which may be a further evidence of a metabolic defect.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aged; Aged, 80 and over; Cerebellum; Cerebral Cortex; Chromatography, High Pressure Liquid; Deoxyguanosine; DNA, Mitochondrial; Humans; Huntington Disease; Middle Aged; Oxidative Stress; Parietal Lobe