Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
Adelson School of Medicine, Ariel University, Ariel 40700, Israel.
Int J Mol Sci. 2020 May 25;21(10):3721. doi: 10.3390/ijms21103721.
-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.
-腺苷蛋氨酸（SAMe）参与大多数生物体内的许多转甲基反应，也是合成单胺神经递质和 N-甲基-D-天冬氨酸（NMDA）受体等物质所必需的。由于其作为表观遗传调节剂的重要作用，我们详细讨论了 DNA 甲基化和去甲基化的过程以及胚胎、胎儿和此后的关键时期的表观遗传修饰。我们还讨论了 SAMe 缺乏的影响以及尝试使用 SAMe 进行治疗，例如治疗重度抑郁症、阿尔茨海默病和其他神经精神疾病。SAMe 是一种批准的食品添加剂，因此也在怀孕期间使用。然而，关于 SAMe 对发育中的胚胎和胎儿可能产生的影响，似乎数据很少。丙戊酸（VPA）是一种耐受性好且有效的抗癫痫药物，也可用作情绪稳定剂。由于其致畸性高，在怀孕期间被禁用。其主要作用机制是组蛋白去乙酰化酶抑制，因此它作为一种表观遗传调节剂，主要作用于大脑。这促使人们进行临床试验，将 VPA 用于治疗退行性脑疾病，如阿尔茨海默病、痴呆、HIV，甚至癌症等其他适应症。因此，我们讨论了 VPA 和 SAMe 对胚胎和出生后早期的可能影响，这段时期是易受表观遗传修饰影响的时期。VPA 也被用作啮齿动物自闭症样行为的诱导剂，我们发现，当在出生后第一周给药时，它会改变基因表达，但当在妊娠第 12 天给孕鼠给药时则不会。相比之下，SAMe 在妊娠第 12 天给药而不是出生后给药时改变了基因表达。如果同时给药，VPA 可预防产前 SAMe 给药引起的基因表达变化，SAMe 可预防早期 postnatal VPA 引起的基因表达变化和自闭症样行为。结论是，VPA 和 SAMe 都是强大的表观遗传修饰剂，对大脑有拮抗作用，未来可能会更广泛地用于治疗各种神经退行性疾病。
