SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies

Ornoy, Asher; Weinstein-Fudim, Liza; Becker, Maria

doi:10.3390/ph15020192

Cited by 8 publications

(6 citation statements)

References 139 publications

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“…Therefore, we extended our study by using the teratogens ISO, VPA and THD and the non-teratogen BSP to identify speci c cardiomyogenic gene signature/pathways by performing transcriptome analysis at the different stages of differentiation, combined with testing of functional alterations during CMs contractions. It is well known that the teratogen THD causes malformations of the limbs [32] whereas VPA induces congenital malformations and is a neurological teratogen [33,34].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-based prediction of drugs, inhibiting cardiomyogenesis in human induced pluripotent stem cells

Cherianidou

Kappenberg

Seidel

et al. 2023

Preprint

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Animal studies for embryotoxicity evaluation of potential therapeutics and environmental factors are complex, costly, and time-consuming. Often, studies are not of human relevance because of species differences. In the present study, we recapitulated the process of cardiomyogenesis in human induced pluripotent stem cells (hiPSCs) by modulation of the Wnt signaling pathway to identify a key cardiomyogenesis gene signature that can be applied to identify compounds and/or stress factors compromising the cardiomyogenesis process. Among the 23 tested teratogens and 16 non-teratogens, we identified three retinoids including 13-cis-retinoic acid that completely block the process of cardiomyogenesis in hiPSCs. Moreover, we have identified an early gene signature consisting of 31 genes and associated biological processes that are severely affected by the retinoids. To predict the inhibitory potential of teratogens and non-teratogens in the process of cardiomyogenesis we established the “Developmental Cardiotoxicity Index” (CDI31g) that accurately differentiates teratogens and non-teratogens to do or do not affect the differentiation of hiPSCs to functional cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

Transcriptome-based prediction of drugs, inhibiting cardiomyogenesis in human induced pluripotent stem cells

Cherianidou

Kappenberg

Seidel

et al. 2023

Preprint

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“…2,3 Lacosamide shares with valproate the ability to induce histone hyperacetylation, which has been suggested as a mechanism of valproate teratogenicity. 4,5 However, the effects of valproate and lacosamide on histone acetylation are mediated by distinct mechanisms. [6][7][8] In a series of in vitro, ex vivo, and in vivo studies, we have consistently demonstrated that the placenta is an important target of antiseizure medications (ASMs).…”

Section: Introductionmentioning

confidence: 99%

“…Over the past years, lacosamide has been increasingly prescribed as an add‐on treatment for pregnant women, although its teratogenicity potential and its neurodevelopmental effects have not been clearly established 2,3 . Lacosamide shares with valproate the ability to induce histone hyperacetylation, which has been suggested as a mechanism of valproate teratogenicity 4,5 . However, the effects of valproate and lacosamide on histone acetylation are mediated by distinct mechanisms 6–8 …”

Section: Introductionmentioning

confidence: 99%

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Lacosamide effects on placental carriers of essential compounds in comparison with valproate: Studies in perfused human placentas

et al. 2022

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Objective Lacosamide is increasingly being prescribed to pregnant women, although its effects on the developing fetus have not been fully clarified yet. Previously, we have shown that several antiseizure medications, particularly valproate, can affect the expression of carriers of essential compounds in placental cells. Here, our aim was to assess the effect of short ex vivo exposure of human placentas to lacosamide on the expression of carriers of essential nutrients required by the human fetus. Methods Placentas were obtained from cesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused over 180 min in the presence of lacosamide at 2.5 μg/ml (10 μmol·L−1, n = 7) or 10 μg/ml (40 μmol·L−1, n = 6), representing low and high therapeutic concentrations, respectively, in the maternal perfusate. Valproate (83 μg/ml, 500 μmol·L−1, n = 6) and the perfusion solution (n = 6) were used as the respective positive and negative controls. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. Results Following a 3‐h perfusion, the mRNA expression of SLC19A1 (encoding the reduced folate carrier 1) was downregulated in placentas treated with 10 μg/ml lacosamide (50%) as compared with the vehicle (p < .05). Across all groups, a significant difference was observed in the expression of SLC19A3 (thiamine transporter 2; 52%, 20%, and 9% decrease by 10 μg/ml lacosamide, 83 μg/ml valproate, and 2.5 μg/ml lacosamide, respectively; p < .05). Significance Lacosamide at high therapeutic concentrations exerted pharmacological effects on the human placenta. Our findings, if manifested in vivo, suggest that lacosamide could potentially affect folate supply to the fetus and support therapeutic monitoring and careful adjustment of lacosamide plasma concentrations during pregnancy.

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“…Moreover, SAMe concentrations were also reduced in rat brain tissue following treatment with monoamine reuptake inhibitors [ 12 ]. SAMe was also suggested to be a potent epigenetic drug [ 8 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Prenatal SAMe Treatment Induces Changes in Brain Monoamines and in the Expression of Genes Related to Monoamine Metabolism in a Mouse Model of Social Hierarchy and Depression, Probably via an Epigenetic Mechanism

Becker

Abaev

Shmerkin

et al. 2022

IJMS

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Reduction in the levels of monoamines, such as serotonin and dopamine in the brain, were reported in patients and animals with depression. SAMe, a universal methyl donor and an epigenetic modulator, is successfully used as an adjunct treatment of depression. We previously found that prenatal treatment with SAMe of Submissive (Sub) mice that serve as a model for depression alleviated many of the behavioral depressive symptoms. In the present study, we treated pregnant Sub mice with 20 mg/kg of SAMe on days 12–15 of gestation and studied the levels of monoamines and the expression of genes related to monoamines metabolism in their prefrontal cortex (PFC) at the age of 3 months. The data were compared to normal saline-treated Sub mice that exhibit depressive-like symptoms. SAMe increased the levels of serotonin in the PFC of female Sub mice but not in males. The levels of 5-HIAA were not changed. SAMe increased the levels of dopamine and of DOPAC in males and females but increased the levels of HVA only in females. The levels of norepinephrine and its metabolite MHPG were unchanged. SAMe treatment changed the expression of several genes involved in the metabolism of these monoamines, also in a sex-related manner. The increase in several monoamines induced by SAMe in the PFC may explain the alleviation of depressive-like symptoms. Moreover, these changes in gene expression more than 3 months after treatment probably reflect the beneficial effects of SAMe as an epigenetic modulator in the treatment of depression.

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SAMe, Choline, and Valproic Acid as Possible Epigenetic Drugs: Their Effects in Pregnancy with a Special Emphasis on Animal Studies

Cited by 8 publications

References 139 publications

Transcriptome-based prediction of drugs, inhibiting cardiomyogenesis in human induced pluripotent stem cells

Transcriptome-based prediction of drugs, inhibiting cardiomyogenesis in human induced pluripotent stem cells

Lacosamide effects on placental carriers of essential compounds in comparison with valproate: Studies in perfused human placentas

Prenatal SAMe Treatment Induces Changes in Brain Monoamines and in the Expression of Genes Related to Monoamine Metabolism in a Mouse Model of Social Hierarchy and Depression, Probably via an Epigenetic Mechanism

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