Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine.

Bottiglieri, Teodoro; Godfrey, P.; Flynn, Tracy; Carney, M. W. P.; Toone, Brian; Reynolds, E. H.

doi:10.1136/jnnp.53.12.1096

Cited by 240 publications

(146 citation statements)

References 15 publications

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“…Previous studies have demonstrated markedly elevated SAM decarboxylase activity, ornithine decarboxylase (ODC) protein and spermidine levels so far [12]. As reported, SAM levels are severely decreased in AD patients' brain and CSF [13]. Moreover, MAT2A gene expression in human hepatocarcinoma cells was modulated by Met deprivation through its conversion into SAM [14].…”

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confidence: 72%

Alzheimer’s disease: amino acid levels and brain metabolic status

2013

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To study brain free amino acids and their relation with dementia we measured, by high-performance liquid chromatography (HPLC), the concentration of eight free amino acids, amines and related compounds. We used temporal cortex (TC) samples obtained from 13 Alzheimer's disease (AD) patients and an equal number of agematched controls (AC). The patterns of free amino acids, amines and related compounds showed significant quantitative changes in AD conditions with respect to healthy ones. In Alzheimer patients, lower levels of GABA were found in the TC (-57 %). Amino acids glutamate (Glu), and aspartate (Asp) concentrations, also appeared significantly reduced in the TC of AD patients (Glu: -30 %; Asp: -40 %) when compared with controls. The significant gap between methionine (Met: -30 %) and cystathionine (Cysta: ?60 %) levels in TC of AD people to controls, might suggest an under/over activity of the transmethylation and transsulphuration pathways, respectively. Glutamine (Gln) and Urea were an exception to this trend because their content was higher in AD patients than in controls. Albeit these compounds may have particular physiological roles, including the possible mediation of synaptic transmission, changes in amino acid levels and related compounds (detected in steady state) suggest a modified metabolic status in brains of AD patients that reveals a reduced function of synaptic transmission. Because several evidences show that patients might display quite different concentrations of neurotransmitters in brain areas, assessing metabolites in different and well-characterized AD stages should be investigated further.

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confidence: 72%

Alzheimer’s disease: amino acid levels and brain metabolic status

2013

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“…Because of this lack of scientific evidences it has been questioned whether SAM crosses cell membrane and/or Blood Brain Barrier (BBB). However, there is evidence which indicates that mice treated with SAM show increased levels of both SAM and SAM/SAH ratio in plasma and brain [29] and that peripherally administered SAM is effective in the treatment of several neuropsychiatric and neurological disorders, with chronic parenteral and oral administration of SAM resulting in increased CNS levels [53]. These evidences strongly indicate that this molecule can readily reach the brain parenchyma, suggesting it penetrates the continuous layer of brain endothelial cells lining the brain microvasculature constituting the BBB.…”

Section: Sam and The Blood Brain Barriermentioning

confidence: 99%

Role of S-adenosylmethionine in the Modulation of Oxidative Stress- Related Neurodegeneration

Cavallaro¹,

Fuso²,

D’Erme³

et al. 2016

Int J Clin Nutr Diet

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S-adenosyl-L-methionine (SAM) is the main biological methyl donor in transmethylation reactions, consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids and RNA. SAM level in the organism decreases with aging and restoring the original levels through exogenous supplementation is an important tool for the improvement of many vital functions. Indeed, SAM deficiency may contribute to the onset of several diseases, i.e. depression, liver diseases, osteoarthritis and senile neurological disorders such as Alzheimer's and Parkinson's diseases. Recent evidences indicate that SAM may have an involvement in oxidative stress, a process which typically involves an alteration of cellular sulfur amino acids homeostasis. SAM is not only the principal methyl donor, but also a precursor of glutathione, the major endogenous antioxidant, whose role in counteracting oxidative stress is well known. In this review we will highlight the role of SAM not just as a methyl-donor but also as a regulator of different metabolic pathways involved in the antioxidant response in brain related disorders. Role of S-adenosylmethionine in the Modulation of Oxidative StressRelated Neurodegeneration Review ArticleOpen Access IntroductionThe interaction between environmental and genetic factors plays a fundamental role in inducing and modulating the aging processes towards brain disorders. Among environmental factors, diet and nutritional lifestyle have a key role in brain health through the alteration of the intake or the bioavailability of metabolites and cofactors. Specific nutritional factors have particular impact on one-carbon metabolism, which is a complex biochemical pathway regulated by the presence of folate, vitamin B12 and B6 (among other metabolites) and leading to the production of S-adenosyl-L-methionine (SAM), the main biological methyl donor in transmethylation reactions, consisting in the transferring of a methyl moiety to different substrates including DNA, proteins, lipids and RNA. This metabolism involves three interrelated biochemical pathways: folate cycle, transsulfuration pathway and methionine cycle. These three metabolic sequences were first combined and correlated in 1964 by Laster's group [1][2][3] giving the integrated point of view of transmethylation and transsulfuration pathways, linking sulfur amino acid metabolism to the provision of methyl groups for many biochemical processes. Normal functioning of this metabolic cycle is essential for growth and development and impairment of this metabolism; transmethylation efficiency is associated with many diseases like cardiovascular diseases [4][5], liver diseases [6-9], neural tube defects [10] and brain diseases [11][12][13][14][15][16]. One-carbon metabolism alterations, low methylation and oxidative stress are all linked to Late Onset Alzheimer's Disease (LOAD) [17][18][19][20][21][22][23][24] Moreover, wide confirmed reports underline the role of SAM dependent reactions in age related neurodegeneration also showi...

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“…Accordingly, SAM constitutes the main biological methyl donor molecule involved in the methylation of DNA, proteins, and phospholipids [19][20][21]. Interestingly, a previous report showed that parenteral and oral SAM treatments promoted an increase in SAM levels in the cerebrospinal fluid of depressed patients, indicating that SAM crosses the blood-brain barrier [22]. Hence, considering the presented data, we previously proposed the use of SAM as an adjunctive therapy in levodopa-treated PD patients to reduce striatal A 2A R levels [23].…”

Section: Introductionmentioning

confidence: 99%

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

Villar-Menéndez

Núñez

Díaz-Sánchez

et al. 2014

Purinergic Signalling

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Adenosine A 2A receptor (A 2A R) is a G proteincoupled receptor enriched in the striatum for which an increased expression has been demonstrated in certain neurological diseases. Interestingly, previous in vitro studies demonstrated that A 2A R expression levels are reduced after treatment with S-adenosyl-L-methionine (SAM), a methyl donor molecule involved in the methylation of important biological structures such as DNA, proteins, and lipids. However, the in vivo effects of SAM treatment on A 2A R expression are still obscure. Here, we demonstrated that 2 weeks of SAM treatment produced a significant reduction in the rat striatal A 2A R messenger RNA (mRNA) and protein content as well as A 2A R-mediated signaling. Furthermore, when the content of 5-methylcytosine levels in the 5′UTR region of ADORA2A was analyzed, this was significantly increased in the striatum of SAM-treated animals; thus, an unambiguous correlation between SAM-mediated methylation and striatal A 2A R expression could be established. Overall, we concluded that striatal A 2A R functionality can be controlled by SAM treatment, an issue that might be relevant for the management of these neurological conditions that course with increased A 2A R expression.

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Cerebrospinal fluid S-adenosylmethionine in depression and dementia: effects of treatment with parenteral and oral S-adenosylmethionine.

Cited by 240 publications

References 15 publications

Alzheimer’s disease: amino acid levels and brain metabolic status

Alzheimer’s disease: amino acid levels and brain metabolic status

Role of S-adenosylmethionine in the Modulation of Oxidative Stress- Related Neurodegeneration

Striatal adenosine A2A receptor expression is controlled by S-adenosyl-L-methionine-mediated methylation

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