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April 2014

S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice.

Methylation reactions linked to homocysteine in the one-carbon metabolism are increasingly elicited in Alzheimer’s disease, although the association of hyperhomocysteinemia and of low B vitamin levels with the disease is still debated. We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production. The present study is aimed at assessing S-adenosylmethionine effects in mice kept under a condition of B vitamin deficiency. To this end, TgCRND8 mice and wild-type littermates were assigned to control or B vitamin deficient diet, with or without S-adenosylmethionine supplementation. We found that S-adenosylmethionine reduced amyloid production, increased spatial memory in TgCRND8 mice and inhibited the upregulation of B vitamin deficiency-induced PSEN1 and BACE1 expression and Tau phosphorylation in TgCRND8 and wild-type mice. Furthermore, S-adenosylmethionine treatment reduced plaque spreading independently on B vitamin deficiency. These results strengthen our previous observations on the possible role of one-carbon metabolism in Alzheimer’s disease, highlighting hyperhomocysteinemia-related mechanisms in dementia onset/progression and encourage further studies aimed at evaluating the use of S-adenosylmethionine as a potential candidate drug for the treatment of the disease.

Neurobiol Aging . 2012 Jul;33(7):1482.e1-16

Methylation status and neurodegenerative markers in Parkinson disease.

BACKGROUND: Increased concentrations of plasma total homocysteine (tHcy) have been associated with age-related diseases, including dementia, stroke, and Parkinson disease (PD). Methylation status might link Hcy metabolism to neurodegenerative proteins in patients with PD. METHODS: We tested blood samples from 87 patients with PD (median age 68 years; 35 men) for tHcy, methylmalonic acid (MMA), vitamin B(12), vitamin B(6), folate, S-adenosyl methionine (SAM), S-adenosyl homocysteine (SAH), and amyloid-beta(1-42). We collected citrate blood from a subset of 45 patients to prepare platelet-rich plasma, and we used washed platelets to prepare cell extracts for amyloid precursor protein (APP) and alpha-synuclein assays. We used brain parenchyma sonography to estimate the substantia nigra echogenic area in a subset of 59 patients. RESULTS: Serum concentrations of tHcy were increased in PD patients (median 14.8 micromol/L). tHcy (beta coefficient = -0.276) and serum creatinine (beta = -0.422) were significant predictors of the ratio of SAM/SAH in plasma (P < 0.01). The plasma SAM/SAH ratio was a significant determinant for DemTect scores (beta = 0.612, P = 0.004). Significant negative correlations were found between concentrations of SAH in plasma and platelet APP and between SAM and platelet alpha-synuclein. A larger echogenic area of the substantia nigra was related to higher serum concentrations of MMA (P = 0.016). CONCLUSIONS: Markers of neurodegeneration (APP, alpha-synuclein) are related to markers of methylation (SAM, SAH) in patients with PD. Better cognitive function was related to higher methylation potential (SAM/SAH ratio).

Clin Chem . 2009 Oct;55(10):1852-60

S-adenosylmethionine prevents oxidative stress and modulates glutathione metabolism in TgCRND8 mice fed a B-vitamin deficient diet.

Oxidative stress, altered glutathione levels, and hyperhomocysteinemia play critical roles in Alzheimer’s disease. We studied the relationships between hyperhomocysteinemia, glutathione, and oxidative stress in TgCRND8 mice maintained in conditions of folate, B12, and B6 deficiency and the effect of S-adenosylmethionine supplementation. We found that hyperhomocysteinemia was correlated with increased reduced/oxidized brain glutathione ratio, with decreased glutathione S-transferase activity and increased lipid peroxidation. S-adenosylmethionine potentiated superoxide dismutase and glutathione S-transferase activity and restored altered brain glutathione and erythrocytes lipid peroxidation. These results underline the importance of S-adenosylmethionine as neuroprotective compound, acting both on methylation and oxidation metabolism.

J Alzheimers Dis . 2010;20(4):997-1002

Methyl nutrients, DNA methylation, and cardiovascular disease.

Diet plays an important role in the development and prevention of cardiovascular disease (CVD), but the molecular mechanisms are not fully understood. DNA methylation has been implicated as an underlying molecular mechanism that may account for the effect of dietary factors on the development and prevention of CVD. DNA methylation is an epigenetic process that provides “marks” in the genome by which genes are set to be transcriptionally activated or silenced. Epigenomic marks are heritable but are also responsive to environmental shifts, such as changes in nutritional status, and are especially vulnerable during development. S-adenosylmethionine is the methyl group donor for DNA methylation and several nutrients are required for the production of S-adenosylmethionine. These methyl nutrients include vitamins (folate, riboflavin, vitamin B12, vitamin B6, choline) and amino acids (methionine, cysteine, serine, glycine). As such, imbalances in the metabolism of these nutrients have the potential to affect DNA methylation. The focus of this review is to provide an overview on the current understanding of the relationship between methyl nutrient status and DNA methylation patterns and the potential role of this interaction in CVD pathology.

Mol Nutr Food Res . 2014 Jan;58(1):172-82

S-adenosylmethionine and 5-methyltetrahydrofolate are associated with endothelial function after controlling for confounding by homocysteine: the Hoorn Study.

OBJECTIVE: To explore to what extent homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine, total folate, 5-methyltetrahydrofolate (5-MTHF), vitamin B12, and vitamin B6 are associated with endothelium-dependent, flow-mediated vasodilation (FMD), and whether these associations are stronger in individuals with diabetes or other cardiovascular risk factors. METHODS AND RESULTS: In this population-based study of 608 elderly people, FMD and endothelium-independent nitroglycerin-mediated dilation (NMD) were ultrasonically estimated from the brachial artery (absolute change in diameter [mum]). High SAM and low 5-MTHF were significantly associated with high and low FMD, respectively (linear regression coefficient, [95% confidence interval]): 48.57 microm (21.16; 75.98) and -32.15 microm (-59.09; -5.20), but high homocysteine was not (-15.11 microm (-42.99; 12.78). High SAM and low 5-MTHF were also significantly associated with high and low NMD, respectively. NMD explained the association of 5-MTHF with FMD but not of SAM. No interactions were observed for diabetes or cardiovascular risk factors. CONCLUSIONS: In this elderly population, both SAM and 5-MTHF are associated with endothelial and smooth muscle cell function. The effect of homocysteine on endothelial function is relatively small compared with SAM and 5-MTHF. The relative impact of SAM, 5-MTHF, and homocysteine, and the mechanisms through which these moieties may affect endothelial and smooth muscle cell function need clarification.

Arterioscler Thromb Vasc Biol . 2005 Apr;25(4):778-84

Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation.

S-adenosylmethionine is a relatively new anti-inflammatory drug with analgesic and anti-depressant effects. Efficacy of 800 mg orally administered s-adenosylmethionine daily versus placebo for six weeks was investigated in 44 patients with primary fibromyalgia in double-blind settings. Tender point score, isokinetic muscle strength, disease activity, subjective symptoms (visual analog scale), mood parameters and side effects were evaluated. Improvements were seen for clinical disease activity (P = 0.04), pain experienced during the last week (P = 0.002), fatigue (P = 0.02), morning stiffness (P = 0.03) and mood evaluated by Face Scale (P = 0.006) in the actively treated group compared to placebo. The tender point score, isokinetic muscle strength, mood evaluated by Beck Depression Inventory and side effects did not differ in the two treatment groups. S-adenosylmethionine has some beneficial effects on primary fibromyalgia and could be an important option in the treatment hereof.

Scand J Rheumatol. 1991;20(4):294-302

Low S-adenosylmethionine concentrations found in patients with severe inflammatory bowel disease.

BACKGROUND: S-adenosy-lmethionine is a methyl donor in many cellular reactions including detoxification of constantly produced hydrogen sulphide in the colon. A reduced capacity to detoxify hydrogen sulphide may be implicated in the pathogenesis of inflammatory bowel disease. S-adenosylmethionine could be low if this assumption is correct. We compared S-adenosylmethionine concentrations in whole blood in patients with severe and moderate inflammatory bowel disease with healthy reference persons. METHODS: S-adenosylmethionine concentrations in whole blood were measured using high-pressure liquid chromatography. Patients with Crohn’s disease (n=21), ulcerative colitis (n=7) and healthy age-matched reference persons (or controls) (n=17) were studied. RESULTS: S-adenosylmethionine concentrations were significantly decreased in patients with severe inflammatory bowel disease (mean 1.10 mg/l) as compared to patients with moderate Crohn’s disease and ulcerative colitis (mean 1.83 mg/l) and reference persons (mean 1.84 mg/l). Statistically significant inverse correlations were found between S-adenosylmethionine concentration and activity index (p<0.01 and R2=0.86) as well as Crohn’s disease activity index (p<0.01 and R2=0.50) scores. CONCLUSIONS: Low concentrations of S-adenosylmethionine were found in patients with severe inflammatory bowel disease. Future studies will show whether S-adenosylmethionine is a marker for disease activity and a possible tool for investigation of sulphur toxicity as a causative mechanism in inflammatory bowel disease.

Clin Chem Lab Med. 2004;42(6):648-53

Double-blind clinical trial of S-adenosylmethionine versus ibuprofen in the treatment of osteoarthritis.

Thirty-six subjects with osteoarthritis of the knee, the hip, and/or the spine were enrolled in a randomized double-blind study. Patients received a daily oral dose of 1,200 mg of S-adenosylmethionine (SAMe) or 1,200 mg of ibuprofen for four weeks. Morning stiffness, pain at rest, pain on motion, crepitus, swelling, and limitation of motion of the affected joints were assessed before and after treatment. The total score obtained by the evaluation of all the individual clinical parameters improved to the same extent in patients treated with SAMe or ibuprofen. Both treatments were well tolerated and no patient from either group withdrew from the study.

Am J Med . 1987 Nov 20;83(5A):81-3

Double-blind, placebo-controlled study of S-adenosyl-L-methionine in depressed postmenopausal women.

S-adenosyl-L-methionine (SAMe) is a naturally occurring substance which is a major source of methyl groups in the brain and has been found in previous studies to be an effective antidepressant. The aim of this study was to assess the efficacy of oral SAMe in the treatment of depressed postmenopausal women in a 30-day double-blind placebo-controlled randomized trial. During the course of the study, 80 women, between the ages of 45 and 59, who were diagnosed as having DSM-III-R major depressive disorder or dysthymia between 6 and 36 months following either
natural menopause or hysterectomy, underwent 1 week of single-blind placebo washout, followed by 30 days of double-blind treatment with either SAMe 1,600 mg/day or placebo. There was a significantly greater improvement in depressive symptoms in the group treated with SAMe compared to the placebo group from day 10 of the study. Side effects were mild and transient.

Psychother Psychosom . 1993;59(1):34-40