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

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

Research output: Contribution to journalArticle

52 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)202-215
Number of pages14
JournalJournal of Molecular Neuroscience
Volume52
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

Keywords

  • CBS
  • DNMT
  • Folic acid
  • Homocysteine
  • MMPs

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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