title: Nutri-epigenetics ameliorates blood-brain barrier damage and neurodegeneration in hyperhomocysteinemia: role of folic acid.
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.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kalani
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Kamat
authors.forename: Srikanth
authors.initials: S
authors.lastname: Givvimani
authors.forename: Kasey
authors.initials: K
authors.lastname: Brown
authors.forename: Naira
authors.initials: N
authors.lastname: Metreveli
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
mesh_terms: D043383:Adenosylhomocysteinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D003541:Cystathionine beta-Synthase / Q000235:genetics; D004032:Diet; D044127:Epigenesis, Genetic; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006579:Heterozygote; D020138:Hyperhomocysteinemia / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000008:administration & dosage / Q000494:pharmacology; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress
chemical_list: D018696:Neuroprotective Agents; D005492:Folic Acid; D008715:Methionine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008780:Methyltransferases; D043383:Adenosylhomocysteinase; D020782:Matrix Metalloproteinases; D003541:Cystathionine beta-Synthase