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 methylenetet-rahydrofolate reductase and an increase in S-adenosylho-mocysteine hydrolase expression, symptoms of oxidative stress, upregulation of DNA methyltransferases, rise in matrix metalloproteinases, a drop in the tissue inhibitors of metallo-proteinases, decreased expression of tight junction proteins, increased permeability of the blood–brain barrier, neuro-degeneration, 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.

Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats

“…GM6001 is a broad-spectrum MMP inhibitor and has been previously tested for various cerebral pathologies; for example, intracerebral hemorrhage [26], altered cellular migration [27], and BBB permeability [28]. MMPs are one of the main culprits involved in cerebral disease progression and we and others have reported that MMP-9, a gelatinase, is associated with impairment of the neurovasculature function, hemorrhagic transformations, neurodegeneration, and BBB disruption [15, 17, 29, 30]. In this current report, we established that attenuating MMP-9 using a synthetic inhibitor, GM6001 rescued hypertension-induced vasculopathy.…”

“…MMPs are expressed in various cell types, including ECs, and are involved in various functions such as; subendothelial matrix (SEM) degradation, extracellular matrix (ECM) and vascular remodeling [15, 16]. We have previously shown the involvement of MMP-9 in cerebrovascular dysfunction [17, 18], by degrading the cerebral vasculature. Our lab including others clearly showed that MMP-9 attenuation can ameliorate cerebral pathologies [15, 18–20].…”

Heterozygous carriers of classical homocystinuria tend to have higher fasting serum homocysteine concentrations than non-carriers in the presence of folate deficiency

“…Another interesting study showed that the supplement of folate could improve Hcy-induced bloodebrain barrier damage and neurodegeneration in hyperhomocysteinemia mouse, which had the heterozygous CBS mutation [22]. According to the previous epidemiological study in Tao, the prevalence of psychotic symptoms is much higher than Han Taiwanese population (Tao tribe: 1.6%, Han Taiwanese: 0.3%) [23].…”

Homocysteine Promotes Intestinal Fibrosis in Rats with Trinitrobenzene Sulfonic Acid-Induced Colitis

“…Hyperhomocysteinemia is known to cause an imbalance between MMPs and TIMPs leading to the accumulation of collagen. Kalani et al [26] showed that a rise in the protein/mRNA expression of MMP-2 and MMP-9 and a drop in the mRNA expression of TIMP-1 and TIMP-2 were observed in the brain tissues of cystathionine-beta-synthase heterozygote knockout methionine-fed mice. Bescond et al [27] found that low molar ratio of Hcy enhanced the activity of MMP-2.…”