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: Anuradha Kalani, Pradip K Kamat, Srikanth Givvimani, Kasey Brown, Naira Metreveli, Suresh C Tyagi, Neetu Tyagi
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 52 Issue 2 Pg. 202-15 (Feb 2014) ISSN: 1559-1166 [Electronic] United States
• PMID: 24122186 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Neuroprotective Agents
• Folic Acid
• Methionine
• Methylenetetrahydrofolate Reductase (NADPH2)
• Methyltransferases
• Adenosylhomocysteinase
• Matrix Metalloproteinases
• Cystathionine beta-Synthase

Topics

• Adenosylhomocysteinase (genetics, metabolism)
• Animals
• Blood-Brain Barrier (drug effects, pathology)
• Cystathionine beta-Synthase (genetics)
• Diet
• Epigenesis, Genetic
• Folic Acid (administration & dosage, pharmacology, therapeutic use)
• Heterozygote
• Hyperhomocysteinemia (diet therapy, genetics, metabolism)
• Matrix Metalloproteinases (genetics, metabolism)
• Methionine (administration & dosage, pharmacology)
• Methylenetetrahydrofolate Reductase (NADPH2) (genetics, metabolism)
• Methyltransferases (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Neuroprotective Agents (administration & dosage, pharmacology, therapeutic use)
• Oxidative Stress