The Regional Concentrations of S‐Adenosyl‐<scp>l</scp>‐Methionine, <i>S</i>‐Adenosyl‐<scp>l</scp>‐Homocysteine, and Adenosine in Rat Brain

Gharib, Abdallah; Sarda, Nicole; Chabannes, B.; Cronenberger, L; Pachéco, H.

doi:10.1111/j.1471-4159.1982.tb08702.x

Cited by 80 publications

(34 citation statements)

References 35 publications

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“…The levels of SAM and SAH measured in our experiments were consistent with those reported by others in postnatal rats (65,66). In adult animals, choline-(19) or methyl-deficient diets (67) lowered hepatic SAM levels, and rats that were fed a diet supplemented with methionine, choline, folic acid, and vitamin B 12 had increased hepatic levels of SAM (18).…”

Section: Discussionsupporting

confidence: 81%

Gestational Choline Deficiency Causes Global and Igf2 Gene DNA Hypermethylation by Up-regulation of Dnmt1 Expression

Kovacheva

Mellott

Davison

et al. 2007

Journal of Biological Chemistry

212

191

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During gestation there is a high demand for the essential nutrient choline. Adult rats supplemented with choline during embryonic days (E) 11-17 have improved memory performance and do not exhibit age-related memory decline, whereas prenatally choline-deficient animals have memory deficits. Choline, via betaine, provides methyl groups for the production of S-adenosylmethionine, a substrate of DNA methyltransferases (DNMTs). We describe an apparently adaptive epigenomic response to varied gestational choline supply in rat fetal liver and brain. S-Adenosylmethionine levels increased in both organs of E17 fetuses whose mothers consumed a choline-supplemented diet. Surprisingly, global DNA methylation increased in choline-deficient animals, and this was accompanied by overexpression of Dnmt1 mRNA. Previous studies showed that the prenatal choline supply affects the expression of multiple genes, including insulin-like growth factor 2 (Igf2), whose expression is regulated in a DNA methylation-dependent manner. The differentially methylated region 2 of Igf2 was hypermethylated in the liver of E17 choline-deficient fetuses, and this as well as Igf2 mRNA levels correlated with the expression of Dnmt1 and with hypomethylation of a regulatory CpG within the Dnmt1 locus. Moreover, mRNA expression of brain and liver Dnmt3a and methyl CpG-binding domain 2 (Mbd2) protein as well as cerebral Dnmt3l was inversely correlated to the intake of choline. Thus, choline deficiency modulates fetal DNA methylation machinery in a complex fashion that includes hypomethylation of the regulatory CpGs within the Dnmt1 gene, leading to its overexpression and the resultant increased global and gene-specific (e.g. Igf2) DNA methylation. These epigenomic responses to gestational choline supply may initiate the long term developmental changes observed in rats exposed to varied choline intake in utero.An adequate supply of essential nutrients involved in the metabolism of methyl groups, including folic acid, vitamin B 12 , and choline, is central for normal development of the fetus. This is perhaps best exemplified by the discovery that the dietary supply of folic acid, a vitamin that acts as a coenzyme in one-carbon transfer pathways, during the periconceptual period is critical in prevention of neural tube defects (1). Studies in animal models (2-5) as well as recent epidemiological investigations in humans (6) indicate that choline intake during gestation is particularly important for the normal development and function of the central nervous system. In a frequently used experimental model that employs offspring of pregnant rats or mice consuming diets of varying choline content during the 7-day period of the second half of gestation (embryonic days E11-17), prenatal choline deficiency causes deficits in certain memory tasks (7), whereas prenatal choline supplementation leads to enhanced memory and attention and prevents agerelated memory decline (7-13). These behavioral changes are accompanied by electrophysiological, neuroanatomical, and neuro...

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Section: Discussionsupporting

confidence: 81%

Gestational Choline Deficiency Causes Global and Igf2 Gene DNA Hypermethylation by Up-regulation of Dnmt1 Expression

Kovacheva

Mellott

Davison

et al. 2007

Journal of Biological Chemistry

212

191

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“…ADA activity decreased with age in the cortex and hippocampus [131], which may induce an increase in Ado levels in elderly people. Indeed, concentrations of Ado exhibit age-dependent alterations in the human cerebral cortex (Ado concentration was higher in the elderly compared with middle-aged subjects) [57] and in all areas of the rat brain [132]. The highest level of SAH in the rat striatum and its modification by age has also been demonstrated [132,133], suggesting that SAHH activity is also unevenly distributed and may change with age in the brain.…”

Section: Modulation Of Adenosine Levels and Epileptic Activity By Metmentioning

confidence: 99%

The Antiepileptic Potential of Nucleosides

Kovács¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Despite newly developed antiepileptic drugs to suppress epileptic symptoms, approximately one third of patients remain drug refractory. Consequently, there is an urgent need to develop more effective therapeutic approaches to treat epilepsy. A great deal of evidence suggests that endogenous nucleosides, such as adenosine (Ado), guanosine (Guo), inosine (Ino) and uridine (Urd), participate in the regulation of pathomechanisms of epilepsy. Adenosine and its analogues, together with non-adenosine (non-Ado) nucleosides (e.g., Guo, Ino and Urd), have shown antiseizure activity. Adenosine kinase (ADK) inhibitors, Ado uptake inhibitors and Ado-releasing implants also have beneficial effects on epileptic seizures. These results suggest that nucleosides and their analogues, in addition to other modulators of the nucleoside system, could provide a new opportunity for the treatment of different types of epilepsies. Therefore, the aim of this review article is to summarize our present knowledge about the nucleoside system as a promising target in the treatment of epilepsy.

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“…These changes may be correlated with varia tions in concentrations of S-adenosyl-L-methionine and S-adenosylhomocysteine. The endogenous SAM level was higher and the SAH level lower in newborn compared with adult rats [20,22], These data suggested that Several reports have studied the ontogen esis of adenosine Ai sites in rat forebrain. Marangos et al [16] showed that high-and low-affinity sites appear to develop in paral lel and the increase of [3H]-CHA binding observed was apparently due to an increase in the number of both high and low affinity rather than to changes in the kinetic of bind ing.…”

Section: Discussionmentioning

confidence: 68%

“…Whole forebrains, cortex or striata used for analysis of SAM, SAH and adenosine concentration, were treated and analysed by high-performance liquid chro matography (HPLC) as previously described [22],…”

Section: Determination Of Sam Sah and Adenosine Levelsmentioning

confidence: 99%

S-Adenosylmethionine, S-Adenosylhomocysteine and Adenosine System

Sarda¹,

Reynaud²,

Gharib³

1989

Dev Pharmacol Ther

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The changes in activity of N-methyltransferase 1 and [3H]-S-adenosylhomocysteine binding were determined in cortical membranes preparations from newborn and 1-, 2- and 10-month-old rats. These parameters were significantly higher: + 130 and 200%, respectively, in 1-day compared to 2-month-old rats (adult). With maturation, S-adenosylmethionine levels decreased (-24%) whereas adenosine levels increased gradually from 0.17 to 6.10 nmol/mg protein in forebrain or whole brain between 1-day and 10-month-old rats. The ontogenesis of adenosine receptors was studied. The A(2) receptors were not detectable at 1 day. For A(1) receptors, K(d) and B(max) increased with age while for A(2) receptors K(d) and B(max) were similar between 9 days and 2 months of age.

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The Regional Concentrations of S‐Adenosyl‐l‐Methionine, S‐Adenosyl‐l‐Homocysteine, and Adenosine in Rat Brain

Cited by 80 publications

References 35 publications

Gestational Choline Deficiency Causes Global and Igf2 Gene DNA Hypermethylation by Up-regulation of Dnmt1 Expression

Gestational Choline Deficiency Causes Global and Igf2 Gene DNA Hypermethylation by Up-regulation of Dnmt1 Expression

The Antiepileptic Potential of Nucleosides

S-Adenosylmethionine, S-Adenosylhomocysteine and Adenosine System

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