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Effect of Sodium Valproate Administration on Brain Neprilysin Expression and Memory in Rats

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Abstract

Alzheimer's disease (AD) is accompanied by memory loss due to neuronal cell death caused by toxic amyloid β-peptide (Aβ) aggregates. In the healthy brain, a group of amyloid-degrading enzymes including neprilysin (NEP) maintain Aβ levels at physiologically low concentrations but, with age and under some pathological conditions, expression and activity of these enzymes decline predisposing to late-onset AD. Hence, up-regulation of NEP might be a viable strategy for prevention of Aβ accumulation and development of the disease. As we have recently shown, inhibitors of histone deacetylases, in particular, valproic acid (VA), were capable of up-regulating NEP expression and activity in human neuroblastoma SH-SY5Y cell lines characterised by very low levels of NEP. In the present study, analysing the effect of i.p. injections of VA to rats, we have observed up-regulation of expression and activity of NEP in rat brain structures, in particular, in the hippocampus. This effect was brain region- and age-specific. Administration of VA has also restored NEP activity and memory deficit in adult rats caused by prenatal hypoxia. This suggests that VA and more specific HDAC inhibitors can be considered as potential pharmaceutical agents for up-regulation of NEP activity and improvement of cognitive functions of ageing brain.

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Acknowledgements

We thank the U.K. MRC, the ARUK and Russian Academy of Science programme “Fundamental Sciences to Medicine” and RFBR (project 10-04-01156) for financial support.

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Authors and Affiliations

  1. Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom

    Natalia N. Nalivaeva, Nikolai D. Belyaev, Natalia Z. Makova & Anthony J. Turner

  2. Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom

    David I. Lewis & Alasdair R. Pickles

  3. I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, RAS, 44 Thorez Avenue, Saint Petersburg, 194223, Russia

    Natalia N. Nalivaeva, Daria I. Bagrova, Nadezhda M. Dubrovskaya, Svetlana A. Plesneva & Igor A. Zhuravin

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  1. Natalia N. Nalivaeva
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  2. Nikolai D. Belyaev
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Correspondence to Natalia N. Nalivaeva.

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Nalivaeva, N.N., Belyaev, N.D., Lewis, D.I. et al. Effect of Sodium Valproate Administration on Brain Neprilysin Expression and Memory in Rats. J Mol Neurosci 46, 569–577 (2012). https://doi.org/10.1007/s12031-011-9644-x

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  • DOI: https://doi.org/10.1007/s12031-011-9644-x

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