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Nutri-epigenetics Ameliorates Blood–Brain Barrier Damage and Neurodegeneration in Hyperhomocysteinemia: Role of Folic Acid

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Abstract

Epigenetic mechanisms underlying nutrition (nutrition epigenetics) are important in understanding human health. Nutritional supplements, for example folic acid, a cofactor in one-carbon metabolism, regulate epigenetic alterations and may play an important role in the maintenance of neuronal integrity. Folic acid also ameliorates hyperhomocysteinemia, which is a consequence of elevated levels of homocysteine. Hyperhomocysteinemia induces oxidative stress that may epigenetically mediate cerebrovascular remodeling and leads to neurodegeneration; however, the mechanisms behind such alterations remain unclear. Therefore, the present study was designed to observe the protective effects of folic acid against hyperhomocysteinemia-induced epigenetic and molecular alterations leading to neurotoxic cascades. To test this hypothesis, we employed 8-weeks-old male wild-type (WT) cystathionine-beta-synthase heterozygote knockout methionine-fed (CBS+/− + Met), WT, and CBS+/− + Met mice supplemented with folic acid (FA) [WT + FA and CBS+/− + Met + FA, respectively, 0.0057-μg g−1 day−1 dose in drinking water/4 weeks]. Hyperhomocysteinemia in CBS+/− + Met mouse brain was accompanied by a decrease in methylenetetrahydrofolate reductase and an increase in S-adenosylhomocysteine hydrolase expression, symptoms of oxidative stress, upregulation of DNA methyltransferases, rise in matrix metalloproteinases, a drop in the tissue inhibitors of metalloproteinases, decreased expression of tight junction proteins, increased permeability of the blood–brain barrier, neurodegeneration, and synaptotoxicity. Supplementation of folic acid to CBS+/− + Met mouse brain led to a decrease in the homocysteine level and rescued pathogenic and epigenetic alterations, showing its protective efficacy against homocysteine-induced neurotoxicity.

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Acknowledgments

This work was supported by National Institutes of Health grants HL107640-NT.

Conflict of Interest

The authors declared no conflict of interest.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, School of Medicine, University of Louisville, 500 South Preston Street, Louisville, KY, 40202, USA

    Anuradha Kalani, Pradip K. Kamat, Srikanth Givvimani, Kasey Brown, Naira Metreveli, Suresh C. Tyagi & Neetu Tyagi

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  1. Anuradha Kalani
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  2. Pradip K. Kamat
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  3. Srikanth Givvimani
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  4. Kasey Brown
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  7. Neetu Tyagi
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Correspondence to Neetu Tyagi.

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Kalani, A., Kamat, P.K., Givvimani, S. et al. Nutri-epigenetics Ameliorates Blood–Brain Barrier Damage and Neurodegeneration in Hyperhomocysteinemia: Role of Folic Acid. J Mol Neurosci 52, 202–215 (2014). https://doi.org/10.1007/s12031-013-0122-5

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