Antyutleniacze w zespole Downa cz.3

Dochodzimy do lat 2005-2006, kiedy to w tezie o konieczności suplementacji pojawiają się zdecydowanie pogłębione hipotezy o stresie tlenowym osób z ZD i szkodach jakie on niesie dla osób z ZD.

W 2005 roku badanie Thiela i Fowkesa skupiło się na pytaniu: co może zredukować upośledzenie osób z ZD? Teza taka wyszła z kwestii nadekspresji genu SOD1 i jego znaczącego udziału w stresie tlenowym osób z ZD. Akumulacja pewnych składników w procesach metabolicznych wynikających z glikacji białek

(co to jest tutaj:  http://pl.wikipedia.org/wiki/Glikacja_bia%C5%82ek )

w trakcie ciąży i już po urodzinach według autorów może być redukowana poprzez takie składniki jak kwas foliowy, witamina B6, witamina C, witamina E, selen, cynk, karnozynę, L-karnitynę, cysteinę, kwas liponowy, aminoguanidynę.

Kolejne badania skupiające się wciąż na tym samym problemie zauważyły dysproporcję w nasileniu tego procesu w zależności od płci. Okazało się, że “ZD oddziaływuje słabiej na kobietę niż na mężczyznę, jednakże w kontekście procesu starzenia, kobieta jest bardziej podatna na stres tlenowy niż mężczyzna.

Wyniki powyższe spowodowały znaczący wzrost liczby badań w tym kierunku. Sięgnięto przede wszystkim po badania biochemiczne poszukując odpowiedzi jak duży poziom stresu tlenowego jest obserwowany, co można wnioskować, jak zachodzi ten proces w zależności od wieku i płci. Lata 2006-2007 dały odpowiedź na te pytania, wskazując bardzo zróżnicowaną statystykę co do głębokości występowania tego procesu. Potwierdziły również, że istnieje możliwość redukcji zagrożeń poprzez kierunkową suplementację budującą metaboliczną równowagę wywołaną nadmiarem genu SOD, który powoduje, że wolne rodniki niszczą komórki nerwowe osób z ZD.

 

Supplement Abstracts

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Biogerontology 7 (4): 211-220 (Aug 2006)

Multiple evidence for an early age pro-oxidant state in Down Syndrome patients

Pallardó FV¹, Degan P, d’Ischia M, Kelly FJ, Zatterale A, Calzone R, Castello G, Fernandez-Delgado R, Dunster C, Lloret A, Manini P, Pisanti MA, Vuttariello E, Pagano G
¹Department of Physiology, University of Valencia, E-46010, Valencia, Spain

Oxidative stress has been associated with Down syndrome (DS) and with its major phenotypic features, such as early ageing. In order to evaluate an in vivo pro-oxidant state, the following analytes were measured in a group of DS patients aged 2 months to 57 years: (a) leukocyte 8-hydroxy-2′-deoxyguanosine (8-OHdG); (b) blood glutathione; (c) plasma levels of: glyoxal (Glx) and methylglyoxal (MGlx); some antioxidants (uric acid, UA, ascorbic acid, AA and Vitamin E), and xanthine oxidase (XO) activity. A significant 1.5-fold increase in 8-OHdG levels was observed in 28 DS patients vs. 63 controls, with a sharper increase in DS patients aged up to 30 years. The GSSG:GSHx100 ratio was significantly higher in young DS patients (< 15 years), in contrast to DS patients aged ≥15 years that showed a significant decrease in the GSSG:GSHx100 ratio ratio vs. controls of the respective age groups. Plasma Glx levels were significantly higher in young DS patients, whereas no significant difference was detected in DS patients aged ≥15 years. Unlike Glx, the plasma levels of MGlx were found to be significantly lower in DS patients vs. controls. A significant increase was observed in plasma levels of UA in DS patients that could be related to an increased plasma XO activity in DS patients. The plasma concentrations of AA were also increased in young (< 15 years) DS patients, but not in older patients vs. controls in the same age range. The levels of Vitamin E in DS patients did not differ from the values determined in control donors. The evidence for a multiple pro-oxidant state in young DS patients supports the role of oxidative stress in DS phenotype, with relevant distinctions according to patients’ ages.

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Clin Chem Lab Med 44 (3): 306-10 (2006)

Markers of oxidative stress in children with Down syndrome

Zitnanova I, Korytar P, Sobotova H, Horakova L, Sustrova M, Pueschel S, Durackova Z
Institute of Chemistry, Biochemistry and Clinical Biochemistry, Medical Faculty, Comenius University, Bratislava, Slovakia.

BACKGROUND: Persons with Down syndrome have increased vulnerability to oxidative stress caused by overexpression of superoxide dismutase, an antioxidant enzyme coded on chromosome 21. Increased oxidative stress may lead to oxidative damage of important macromolecules. We monitored this damage by measuring levels of different biomarkers of oxidative stress (protein carbonyls and 4-hydroxy-2-nonenal), as well as plasma antioxidant capacity, in children with Down syndrome. A total of 20 children with Down syndrome and 18 healthy individuals were recruited for this purpose. METHODS: Plasma protein carbonyls were measured using an ELISA technique, 4-hydroxy-2-nonenal was monitored by HPLC and the antioxidant capacity was evaluated using a ferric reducing ability of plasma (FRAP) assay. RESULTS: We found that children with Down syndrome had significantly elevated levels of protein carbonyls compared to healthy controls (p < 0.01). Levels of 4-hydroxy-2-nonenal and antioxidant capacity were similar in both groups. CONCLUSION: Our results on oxidative damage to proteins confirm the assumption of increased oxidative stress in individuals with Down syndrome.

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Mayo Clin Proc 80 (12): 1607-11 (2005 Dec)

Oxidative stress and hematologic and biochemical parameters in individuals with Down syndrome

Garcez ME, Peres W, Salvador M
Instituto de Biotecnologia e Departamento de Ciencias Biomedicas, Universidade de Caxias do Sul, RS, Brazil

OBJECTIVE: To evaluate the levels of thiobarbituric acid reactive substances (TBARS), uric acid, and seric superoxide dismutase and catalase activities, as well as total serum iron, total iron-binding capacity (TIBC), erythrocyte osmotic fragility, and hemograms in people with Down syndrome. PARTICIPANTS AND METHODS: The study sampled (July to December 2003) 50 people with Down syndrome and 50 individuals without Down syndrome (control group) matched by age and sex. The levels of TBARS were measured by the TBARS method. Serum superoxide dismutase and catalase activities and uric acid levels were determined spectrophotometrically. Erythrocyte osmotic fragility was assessed by the percentage of hemolysis. Hemograms, total serum iron level, and TIBC were determined with automated systems. RESULTS: The results showed that levels of TBARS, uric acid, and seric superoxide dismutase and catalase activities were higher in the Down syndrome group compared with the control group. We also observed a slight increase in erythrocyte osmotic fragility in the Down syndrome group, but the total serum iron levels, TIBC, and hemograms for both groups were within the age-related reference values. CONCLUSION: This was the first time, to our knowledge, that increases in seric superoxide dismutase and catalase activities were observed in people with Down syndrome. Although other studies are necessary, our results add to the understanding of the mechanisms responsible for the increased oxidative stress observed in individuals with Down syndrome and may be useful in supporting future antioxidant therapies that will improve the lives of people with Down syndrome.

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Life Sci 76 (12): 1407-26 (2005 Feb 4)

Anti-oxidant gene expression imbalance, aging and Down syndrome

Sinha S.
Department of Biotechnology, Brain Insights, Inc., 17801 Sky Park Circle # K, Irvine, California 92614, USA

The expression of copper zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), glutathione peroxidase (GPx), and catalase (CAT) genes have been detected in human skin fibroblast cells for 2 year normal child (control), 50 year old normal male and female and a 1 year old Down Syndrome (DS) male and female with established trisomy karyotype using the RT-PCR technique. Differential expression of these genes is quantified individually against a beta-Actin gene that has been employed as an internal control. The immunoblotting of cell lysate proteins with polyclonal antibodies exhibit SOD1 (16 kD), SOD2 (40 kD), GPx (23 and 92 kD), CAT (64 kD), and Actin (43 kD) as translational products. The results demonstrate that the enhancement in the level of mRNAs encoding SOD1 in DS male and female, as well as aged male and female are 51, 21, 31 and 50% respectively compared to the normal child (control). In SOD2, DS male and female display higher (176%) and lower (26%) levels of expression whereas aged male and female exhibit enhanced levels of expression (66 and 119%) respectively compared to the control. This study demonstrates that DS affects the female less than the male whereas in the aging process, the female is more prone to oxidative damage than the male. These results not only indicate that the level of GPx mRNA is constant except in DS male, which shows a downward regulation but that even CAT mRNA is upward regulated in aged as well as in DS males and females. These disproportionate changes in anti-oxidant genes, which are incapable of coping with over expressed genes, may contribute towards the aging process, dementia and Down syndrome.

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Med Hypotheses 64 (3): 524-32 (2005)

Can cognitive deterioration associated with Down syndrome be reduced?

Thiel R, Fowkes SW
Center for Natural Health Research, Down Syndrome-Epilepsy Foundation, 1248 E. Grand Avenue, Suite A, Arroyo Grande, CA 93420, USA

Individuals with Down syndrome have signs of possible brain damage prior to birth. In addition to slowed and reduced mental development, they are much more likely to have cognitive deterioration and develop dementia at an earlier age than individuals without Down syndrome. Some of the cognitive impairments are likely due to post-natal hydrogen peroxide-mediated oxidative stress caused by overexpression of the superoxide dismutase (SOD-1) gene, which is located on the triplicated 21st chromosome and known to be 50% overexpressed. However, some of this disability may also be due to early accumulation of advanced protein glycation end-products, which may play an adverse role in prenatal and postnatal brain development. This paper suggests that essential nutrients such as folate, vitamin B6, vitamin C, vitamin E, selenium, and zinc, as well as alpha-lipoic acid and carnosine may possibly be partially preventive. Acetyl-L-carnitine, aminoguanidine, cysteine, and N-acetylcysteine are also discussed, but have possible safety concerns for this population. This paper hypothesizes that nutritional factors begun prenatally, in early infancy, or later may prevent or delay the onset of dementia in the Down syndrome population. Further examination of these data may provide insights into nutritional, metabolic and pharmacological treatments for dementias of many kinds. As the Down syndrome population may be the largest identifiable group at increased risk for developing dementia, clinical research to verify the possible validity of the prophylactic use of anti-glycation nutrients should be performed. Such research might also help those with glycation complications associated with diabetes or Alzheimer’s.