Original Contribution
α-Tocopherol suppresses lipid peroxidation and behavioral and cognitive impairments in the Ts65Dn mouse model of Down syndrome

https://doi.org/10.1016/j.freeradbiomed.2011.03.023Get rights and content

Abstract

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 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.

Section snippets

Animals

All mice were a result of crossing B6EiC3Sn a/A-Ts(17<16>)65Dn (Ts65Dn) females (originally obtained from The Jackson Laboratory, Bar Harbor, ME, USA) to C57BL/6JEi × C3H/HeSnJ (B6EiC3Sn) F1 males (The Jackson Laboratory). Control mice (2N, diploid) for this experiment were normosomic littermates of the Ts65Dn mice with the same genetic background (B6EiC3Sn). Animals from the same litter were group-housed and maintained on a 12-h/12-h light/dark schedule. All mice were chromosomally genotyped.

α-Tocopherol-supplemented diet improves the performance of Ts65Dn mice on the elevated-plus maze

The results of the elevated-plus maze test indicated significant differences between control-diet-fed 2N mice and Ts65Dn mice (Fig. 1). The preference for open versus closed arms is expressed as an open arm ratio, calculated as the percentage of time spent in the open arms (open arm/(open + closed arm)). The open arm ratio for control-diet-fed Ts65Dn mice (41.7%) was approximately eight times higher than that of the control-diet-fed 2N mice (5.2%). α-Tocopherol supplementation reduced the open

Discussion

This study attempted to characterize the behavioral effects induced by chronic supplementation with α-tocopherol from the embryonic stage in Ts65Dn mice. To the best of our knowledge, no previous study has used a mouse model to examine the effects of α-tocopherol from the embryonic stage. Ts65Dn mice fed a control diet exhibited the following behavioral features in comparison to control-diet 2N mice: (a) less anxiety and regardlessness in the elevated-plus maze task, (b) impaired spatial

Acknowledgments

This study was partially supported by Grant-in-Aid for Young Scientists (A) 22680051 and Scientific Research (B) 22300242 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

References (44)

  • H. Shi et al.

    Comparative study on dynamics of antioxidative action of α-tocopheryl hydroquinone, ubiquinol, and α-tocopherol against lipid peroxidation

    Free Radic. Biol. Med.

    (1999)
  • H.A. Lorenzi et al.

    Hippocampal hypocellularity in the Ts65Dn mouse originates early in development

    Brain Res.

    (2006)
  • K. Uchida et al.

    Acrolein is a product of lipid peroxidation reaction: formation of free acrolein and its conjugate with lysine residues in oxidized low density lipoproteins

    J. Biol. Chem.

    (1998)
  • K. Ma et al.

    Altered brain lipid composition in cyclooxygenase-2 knockout mouse

    J. Lipid Res.

    (2007)
  • G. Ravaglia et al.

    Plasma tocopherols and risk of cognitive impairment in an elderly Italian cohort

    Am. J. Clin. Nutr.

    (2008)
  • M.E. Murphy et al.

    Antioxidant depletion in aortic crossclamping ischemia: increase of the plasma α-tocopheryl quinone/α-tocopherol ratio

    Free Radic. Biol. Med.

    (1992)
  • N. Rueda et al.

    Effects of chronic administration of SGS-111 during adulthood and during the pre- and post-natal periods on the cognitive deficits of Ts65Dn mice, a model of Down syndrome

    Behav. Brain Res.

    (2008)
  • S. Roy et al.

    Vitamin E sensitive genes in the developing rat fetal brain: a high-density oligonucleotide microarray analysis

    FEBS Lett.

    (2002)
  • J. Lockrow et al.

    Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model

    Exp. Neurol.

    (2009)
  • M. Betti et al.

    Maternal dietary loads of α-tocopherol depress protein kinase C signaling and synaptic plasticity in rat postnatal developing hippocampus and promote permanent deficits in adult offspring

    J. Nutr. Biochem.

    (2011)
  • R.S. Chapman et al.

    Behavioral phenotype of individuals with Down syndrome

    Ment. Retard. Dev. Disabil. Res. Rev.

    (2000)
  • M.P. Cosgrave et al.

    Determinants of aggression, and adaptive and maladaptive behavior in older people with Down's syndrome with and without dementia

    J. Intellect. Disabil. Res.

    (1999)
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