S-Adenosine Methionine (SAMe) and Valproic Acid (VPA) as Epigenetic Modulators: Special Emphasis on their Interactions Affecting Nervous Tissue during Pregnancy
Open Access
- 25 May 2020
- journal article
- review article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 21 (10), 3721
- https://doi.org/10.3390/ijms21103721
Abstract
S-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.Keywords
This publication has 144 references indexed in Scilit:
- Lipid Peroxidation and Depressed Mood in Community-Dwelling Older Men and WomenPLOS ONE, 2013
- Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood AutismJAMA, 2013
- Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brainTranslational Psychiatry, 2012
- DNA Methylation and Demethylation in MammalsJournal of Biological Chemistry, 2011
- Curcumin reverses corticosterone-induced depressive-like behavior and decrease in brain BDNF levels in ratsNeuroscience Letters, 2011
- Regulation of chromatin by histone modificationsCell Research, 2011
- Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depressionMolecular Psychiatry, 2010
- Valproic acid in pregnancy: How much are we endangering the embryo and fetus?Reproductive Toxicology, 2009
- Mammalian DNA Methyltransferases: A Structural PerspectiveStructure, 2008
- S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylationHepatology, 2008