TY - JOUR
T1 - Nutri-epigenetics Ameliorates Blood-Brain Barrier Damage and Neurodegeneration in Hyperhomocysteinemia
T2 - Role of Folic Acid
AU - Kalani, Anuradha
AU - Kamat, Pradip K.
AU - Givvimani, Srikanth
AU - Brown, Kasey
AU - Metreveli, Naira
AU - Tyagi, Suresh C.
AU - Tyagi, Neetu
N1 - Funding Information:
Acknowledgments This work was supported by National Institutes of Health grants HL107640-NT.
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - CBS
KW - DNMT
KW - Folic acid
KW - Homocysteine
KW - MMPs
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U2 - 10.1007/s12031-013-0122-5
DO - 10.1007/s12031-013-0122-5
M3 - Article
C2 - 24122186
AN - SCOPUS:84894253916
SN - 0895-8696
VL - 52
SP - 202
EP - 215
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 2
ER -