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.