dinoprost and Down-Syndrome

Lipid peroxidation may be a marker of free-radical-mediated injury associated with Alzheimer's disease (AD). We aimed to investigate whether changes in lipid peroxidation is associated with cognitive decline in individuals with Down syndrome over a 4-year period.. Thirty-two adults with DS participated in a longitudinal study with urinary isoprostane 8,12-iso-iPF2alpha (iPF2alpha) assays at baseline and four years follow-up. Informants rated their functional ability and memory function and the adults with DS attempted assessments of language skills and memory. Twenty-six individuals completed assessments of memory (Modified Memory Object Task, MOMT), adaptive behavior (ABAS), and receptive vocabulary (British Picture vocabulary, BPVS) at both time-points.. Overall change in iPF2alpha level was negatively correlated with change in the MOMT score (Spearman's Rho =  -0.576, p = 0.006), i.e., increased lipid peroxidation was correlated with worse memory functioning over time. An increase of ≥ 0.02 ng/mg creatinine iPF2α had good sensitivity (85.7%), positive predictive value (75%,), specificity (85.7%) and negative predictive value (92.3%) for memory decline.. Change in iPF2alpha over time may have potential as a biomarker for memory decline in Down syndrome and potentially also help to track progression of MCI to AD in the general population.

Topics: Adolescent; Adult; Biomarkers; Cognition; Dinoprost; Down Syndrome; Enzyme Activation; Female; Follow-Up Studies; Humans; Male; Memory Disorders; Oxidation-Reduction; Oxidative Stress; Psychometrics; Young Adult

It is widely accepted that oxidative stress is involved in the pathogenesis of Down syndrome, but the effectiveness of antioxidant treatment remains inconclusive. We tested whether chronic administration of α-tocopherol ameliorates the cognitive deficits exhibited by Ts65Dn mice, a mouse model of Down syndrome. α-Tocopherol was administered to pregnant Ts65Dn females, from the day of conception throughout the pregnancy, and to pups over their entire lifetime, from birth to the end of the behavioral testing period. Cognitive deficits were confirmed for Ts65Dn mice fed a control diet, revealing reduced anxiety or regardlessness in the elevated-plus maze task test and spatial learning deficits in the Morris water maze test. However, supplementation with α-tocopherol attenuated both cognitive impairments. In addition, we found that levels of 8-iso-prostaglandin F(2α) in brain tissue and hydroxyoctadecadienoic acid and 7-hydroxycholesterol in the plasma of Ts65Dn mice were higher than those of control mice. Supplementation with α-tocopherol decreased levels of lipid peroxidation products in Ts65Dn mice. Furthermore, we found out that α-tocopherol improved hypocellularity in the hippocampal dentate gyrus of Ts65Dn mice. These results imply that α-tocopherol supplementation from an early stage may be an effective treatment for the cognitive deficits associated with Down syndrome.

Topics: alpha-Tocopherol; Animals; Animals, Newborn; Brain; Cognition Disorders; Dinoprost; Disease Models, Animal; Down Syndrome; Fatty Acids, Unsaturated; Female; Free Radicals; Hippocampus; Hydroxycholesterols; Lipid Peroxidation; Maze Learning; Mice; Mice, Neurologic Mutants; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Space Perception

It has been suggested that oxidative stress plays a key role in the pathogenesis of Down syndrome (DS). However, urinary biomarkers of oxidative stress have been little studied in this condition. Thus, we aimed to assess a set of urinary oxidative/nitrosative stress biomarkers in children with DS, with and without hypothyroidism, which comprise: 8-hydroxy-2'-deoxyguanosine (8-OHdG), isoprostane 15-F(2t)-IsoP, thiobarbituric acid-reacting substances (TBARS), advanced glycation end products (AGEs), dityrosine (diTyr), hydrogen peroxide (H(2)O(2)) and nitrite/nitrate (NOx).. Fluorimetric and spectrophotometric assays were performed in children with DS (n=26), some of them taking levothyroxine for hypothyroidism (n=7), and their non-Down siblings (n=19).. We found that only levels of diTyr were increased in DS, although no differences were obtained when hypothyroid DS children were excluded. Levels of 8-OHdG, 15-F(2t)-IsoP, TBARS, AGEs, H(2)O(2) and NOx did not differ neither between DS and controls nor between hypothyroid DS children and DS without hypothyroidism diagnosed. However, diTyr is increased in hypothyroid DS children compared with controls. Negative correlations with age were obtained for 8-OHdG, diTyr and NOx in DS and controls and for 8-OHdG, 15-F(2t)-IsoP, TBARS and AGEs in DS.. Increased oxidative stress in children with DS cannot be explained by the urinary levels of 8-OHdG, 15-F(2t)-IsoP, TBARS, AGEs, diTyr, H(2)O(2) and NOx, at least with the assays used. Nonetheless, urinary diTyr could be used as oxidative/nitrosative stress biomarker in hypothyroid DS children. The present work presents evidence of a probable renal impairment in children with DS receiving levothyroxine for hypothyroidism.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adolescent; Biomarkers; Child; Child, Preschool; Deoxyguanosine; Dinoprost; Down Syndrome; Female; Glycation End Products, Advanced; Humans; Hydrogen Peroxide; Hypothyroidism; Lipid Peroxidation; Male; Nitrates; Nitrites; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Tyrosine

We aimed to study the hypothesis that high levels of superoxide dismutase (SOD1), previously reported in Down syndrome, would be associated with poorer ability on cognitive tests. Compensatory rises in the activity of glutathione peroxidase (GPx) was expected to be associated with better ability, so that a high ratio between SOD1 and GPx was hypothesised to be the best predictor of poorer cognitive performance.. 32 adults with Down syndrome between the ages of 18 and 45 years donated blood samples for SOD1 and GPx assays and urine for Isoprostane 8,12-iso-iPF(2alpha)-VI assay, a specific biomarker of lipid peroxidation in vivo. Informants rated functional ability and memory function for all participants, and those adults with DS that was able to, also completed psychometric assessments of language ability and memory.. Neither SOD1 nor GPx were related to the elevated markers of lipid peroxidation previously described in living adults with DS, and our hypothesis that an increased SOD1/GPx ratio would be correlated with worse performance on cognitive or functional measures was not supported. Contrary to our hypothesis, we found that low SOD1/GPx ratios were associated with worse memory ability, which remained after controlling for confounders such as sex, age or nutritional supplements.. The anti-oxidant system in DS is implicated in the cognitive phenotype associated with the chromosomal disorder, but the variations in the phenotype could result from several possible gene or gene product interactions. Much further research is required before it will be possible to counteract the oxidative stress associated with DS.

Topics: Adolescent; Adult; Cognition; Dinoprost; Down Syndrome; Female; Glutathione Peroxidase; Humans; Language Tests; Lipid Peroxidation; Male; Memory; Middle Aged; Oxidative Stress; Superoxide Dismutase

Postmortem and in vitro studies have shown that oxidative stress plays a role in the pathogenesis of many of the clinical features of Down's syndrome. The isoprostane 8,12-iso-iPF2alpha-VI is a specific marker of lipid peroxidation. We found elevated levels of this isoprostane in urine samples of subjects with Down's syndrome compared with those of matched controls, which correlated with the duration of the disease. These results suggest that increased in vivo lipid peroxidation is a prominent component early in the course of Down's syndrome.

Topics: Adolescent; Analysis of Variance; Child; Child, Preschool; Dinoprost; Down Syndrome; Female; Humans; Infant; Lipid Peroxidation; Male; Sensitivity and Specificity