Trimethylglycine (TMG)

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Information on nutritional supplements people with ALS have been taking

Effects on ALS[edit]

Examine.com: The main mechanisms of betaine are either its usage as a methyl donor, where it either directly donates a methyl group to reduce homocysteine into L-methionine (seen as cardioprotective) or it increases bodily levels of S-Adenosyl Methionine (SAMe) or active folate molecules, and those two can then go on to donate methyl groups to other parts of the body. Due to this, supplementation of betaine is able to indirectly support whole-body methylation, and directly support a reduction in homocysteine (which is reliably observed following moderate to high dose supplementation. The other major mechanism is that betaine is as an osmolyte, or a molecule that is shuttled in and out of a cell to affect its hydration status. Similar to Creatine, increased intracellular concentrations of betaine promote cell hydration and resilience to stressors.

In conclusion, several types of evidence show that accumulation of homocysteine may increase the risk and progression of motoneuronal degeneration. If this is confirmed, early interventions to decrease homocysteine levels may be useful to modify ALS progression and possibly onset. [1]

[...] at the mammalian neuromuscular junction homocysteine largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of homocysteine and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS. [2]

Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor, but also as a partial antagonist of the glycine coagonist site. [3]

These results suggest that betaine contributes to both the decrease in the plasma homocysteine concentration and the suppression of plasma homocysteine elevation through the activation of liver BHMT. [4]

Significant lowering of homocysteine concentration after the drinking period was found in subjects with concurrent folate and betaine supplementation. Vitamin B12 and vitamin B₆ supplementation did not lead to a statistically significant change in homocysteine. According to a multiple linear regression model, the homocysteine change in the wine-only group was mainly determined by the interaction between the higher baseline homocysteine concentration and the change in dimethylglycine levels. Folate and betaine can attenuate possible adverse effects of moderate alcohol consumption. Dimethylglycine should be interpreted together with data on alcohol consumption and homocysteine concentration.[5]v

The study recruited patients with stage 1 essential hypertension and hyper-homocysteinemia (HCys ≥15 μmol/L), without a history of cardiovascular and cerebrovascular disease. They were sequentially randomized to receive a combined nutraceutical containing 400 μg folate-6-5-methyltetrahydrofolate, 3 mg vitamin B6, 5 μg vitamin B12, 2.4 mg vitamin B2, 12.5 mg zinc and 250 mg betaine (Normocis400®) once daily for two months, or supplementation with highly dosed folic acid (5 mg/day) (control group). Differences in serum HCys values were compared by ANOVA for repeated measures. A significant HCys reduction in comparison to baseline was found in both groups at the end of the study treatment, from 21.5±8.7 to 10.0±1.7 μmol/L for Normocis400® subjects (p less than 0.0001), and from 22.6±6.2 to 14.3±2.8 μmol/L for controls (p less than 0.0001). HCys reduction was significantly higher among patients treated with Normocis400® (p less than 0.035). The ideal HCys level (i.e. less than 10 μmol/L) was reached in 55.8% of cases in theNormocis400® group, and it was significantly higher than in controls. No side effects were observed in either treatment group. Randomized clinical trials are ongoing to test the effect of folate, B6, and B12 supplementation in primary prevention of cardiovascular and cerebrovascular events. In the meantime, especially when the ideal HCys level is far from being reached, Normocis400® appears to be safe, well tolerated and effective in reducing HCys levels. [6]

Prior to supplementation, piglets had lower concentrations of plasma folate, betaine, and choline compared to baseline with no change in homocysteine. Post-supplementation, phenylalanine oxidation levels were 20-46 % lower with any methyl donor supplementation (P = 0.006) with no difference among different supplementation groups. Furthermore, both methyl donors led to similarly lower concentrations of homocysteine following supplementation (P < 0.05). [7]

Interestingly, treatment with betaine significantly inhibited Hcy-induced MMP-9 activity in the frontal cortex but not in the hippocampus after acute Hcy injection. These results suggest that the changes in MMP-9 activity after betaine treatment might have been partially responsible for the amelioration of the memory deficits and that MMP-9 might be a candidate therapeutic target for HHcy. [8]

The present results show beneficial antioxidant and methyl donor properties of betaine versus oxidative stress and hyperhomocysteinemia induced by levodopa and benserazide in an animal model. [9]

Homocysteine metabolism[edit]

Homocysteine_metabolism.png

Discussion threads on the ALSTDI forum[edit]

Where to get it[edit]

References[edit]

  1. Zoccolella et al.: Homocysteine levels and amyotrophic lateral sclerosis: A possible link. Amyotroph Lateral Scler 2010;11:140-7. PMID: 19551535. DOI. Homocysteine (Hcy) exerts multiple neurotoxic mechanisms that have also been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). We reviewed the published evidence to assess possible correlations between Hcy and ALS. A Medline literature search was performed to identify all studies on Hcy and ALS or motor neurons published from 1 January 1966 through 28 February 2009. Twelve studies (one in vitro, eight in vivo, and three studies on human subjects) were reviewed. The in vitro and in vivo animal studies showed that Hcy can damage motor neurons by inducing oxidative stress and stimulating excitotoxic receptors. In preliminary studies on human subjects, ALS subjects had higher median Hcy levels compared to age- and sex-matched controls. Higher Hcy levels were also correlated with a possible marker of disease progression. Finally, a short-term treatment with a high dose of methylcobalamin, which reduces Hcy levels, was effective in improving compound motor action potentials in patients with ALS. In conclusion, several types of evidence show that accumulation of Hcy may increase the risk and progression of motoneuronal degeneration. If this is confirmed, early interventions to decrease Hcy levels may be useful to modify ALS progression and possibly onset.
  2. Bukharaeva et al.: Homocysteine aggravates ROS-induced depression of transmitter release from motor nerve terminals: potential mechanism of peripheral impairment in motor neuron diseases associated with hyperhomocysteinemia. Front Cell Neurosci 2015;9:391. PMID: 26500495. DOI. Homocysteine (HCY) is a pro-inflammatory sulphur-containing redox active endogenous amino acid, which concentration increases in neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). A widely held view suggests that HCY could contribute to neurodegeneration via promotion of oxidative stress. However, the action of HCY on motor nerve terminals has not been investigated so far. We previously reported that oxidative stress inhibited synaptic transmission at the neuromuscular junction, targeting primarily the motor nerve terminals. In the current study, we investigated the effect of HCY on oxidative stress-induced impairment of transmitter release at the mouse diaphragm muscle. The mild oxidant H2O2 decreased the intensity of spontaneous quantum release from nerve terminals (measured as the frequency of miniature endplate potentials, MEPPs) without changes in the amplitude of MEPPs, indicating a presynaptic effect. Pre-treatment with HCY for 2 h only slightly affected both amplitude and frequency of MEPPs but increased the inhibitory potency of H2O2 almost two fold. As HCY can activate certain subtypes of glutamate N-methyl D-aspartate (NMDA) receptors we tested the role of NMDA receptors in the sensitizing action of HCY. Remarkably, the selective blocker of NMDA receptors, AP-5 completely removed the sensitizing effect of HCY on the H2O2-induced presynaptic depressant effect. Thus, at the mammalian neuromuscular junction HCY largely increases the inhibitory effect of oxidative stress on transmitter release, via NMDA receptors activation. This combined effect of HCY and local oxidative stress can specifically contribute to the damage of presynaptic terminals in neurodegenerative motoneuron diseases, including ALS.
  3. Lipton et al.: Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc. Natl. Acad. Sci. U.S.A. 1997;94:5923-8. PMID: 9159176. Severely elevated levels of total homocysteine (approximately millimolar) in the blood typify the childhood disease homocystinuria, whereas modest levels (tens of micromolar) are commonly found in adults who are at increased risk for vascular disease and stroke. Activation of the coagulation system and adverse effects of homocysteine on the endothelium and vessel wall are believed to underlie disease pathogenesis. Here we show that homocysteine acts as an agonist at the glutamate binding site of the N-methyl-D-aspartate receptor, but also as a partial antagonist of the glycine coagonist site. With physiological levels of glycine, neurotoxic concentrations of homocysteine are on the order of millimolar. However, under pathological conditions in which glycine levels in the nervous system are elevated, such as stroke and head trauma, homocysteine's neurotoxic (agonist) attributes at 10-100 microM levels outweigh its neuroprotective (antagonist) activity. Under these conditions neuronal damage derives from excessive Ca2+ influx and reactive oxygen generation. Accordingly, homocysteine neurotoxicity through overstimulation of N-methyl-D-aspartate receptors may contribute to the pathogenesis of both homocystinuria and modest hyperhomocysteinemia.
  4. Yagisawa et al.: Effects of chronic betaine ingestion on methionine-loading induced plasma homocysteine elevation in rats. J. Nutr. Sci. Vitaminol. 2006;52:194-9. PMID: 16967763. The effects of chronic betaine ingestion were investigated in rats. Rats were fed an experimental diet containing 5% betaine for 4 wk and methionine was intravenously administered. The elevations of plasma homocysteine were assessed by comparing the increments to the initial measured value and the positive incremental area under the plasma homocysteine concentration curve over the 240-min post-methionine-loading period (deltaAUC0-240). In the betaine-ingesting rats, deltaAUC0-240 was significantly lower than in the control group (48% of the control), and the increments of plasma homocysteine were also lower compared with the control, especially 15-30 min after methionine loading. Choline, a precursor of betaine, did not alter the plasma homocysteine elevation. In a definite period immediately after methionine loading, carnitine, a methyl-group-rich amino acid, induced a significant increase of plasma homocysteine, compared to the control. Moreover, plasma homocysteine concentration was significantly decreased by 4 wk of betaine ingestion. Betaine enhanced liver BHMT activity whereas choline and carnitine did not show any effects on BHMT activity. These results suggest that betaine contributes to both the decrease in the plasma homocysteine concentration and the suppression of plasma homocysteine elevation through the activation of liver BHMT.
  5. Rajdl et al.: Effect of Folic Acid, Betaine, Vitamin B₆, and Vitamin B12 on Homocysteine and Dimethylglycine Levels in Middle-Aged Men Drinking White Wine. Nutrients 2016;8:. PMID: 26771632. DOI. UNLABELLED: Moderate regular consumption of alcoholic beverages is believed to protect against atherosclerosis but can also increase homocysteine or dimethylglycine, which are putative risk factors for atherosclerosis. We aimed (1) to investigate the effect of alcohol consumption on vitamins and several metabolites involved in one-carbon metabolism; and (2) to find the most effective way of decreasing homocysteine during moderate alcohol consumption. METHODS: Male volunteers (n = 117) were randomly divided into five groups: the wine-only group (control, 375 mL of white wine daily for one month) and four groups combining wine consumption with one of the supplemented substances (folic acid, betaine, and vitamins B12 or B₆). Significant lowering of homocysteine concentration after the drinking period was found in subjects with concurrent folate and betaine supplementation. Vitamin B12 and vitamin B₆ supplementation did not lead to a statistically significant change in homocysteine. According to a multiple linear regression model, the homocysteine change in the wine-only group was mainly determined by the interaction between the higher baseline homocysteine concentration and the change in dimethylglycine levels. Folate and betaine can attenuate possible adverse effects of moderate alcohol consumption. Dimethylglycine should be interpreted together with data on alcohol consumption and homocysteine concentration.
  6. Mazza et al.: Nutraceutical approaches to homocysteine lowering in hypertensive subjects at low cardiovascular risk: a multicenter, randomized clinical trial. J. Biol. Regul. Homeost. Agents 2016;30:921-927. PMID: 27655522. Although the role of homocysteine (HCys) in secondary cardiovascular prevention has been scaled down, hyper-homocysteinemia remains a risk factor for cerebrovascular events. The aim of this study was to investigate the efficacy of nutraceuticals in lowering HCys serum levels versus a conventional vitamin supplementation in hypertensive subjects at low cardiovascular risk. One-hundred and four patients (mean age 62.8±14.5 years, 63.5% males), 52 for each treatment group, were enrolled. The study recruited patients with stage 1 essential hypertension and hyper-homocysteinemia (HCys ≥15 μmol/L), without a history of cardiovascular and cerebrovascular disease. They were sequentially randomized to receive a combined nutraceutical containing 400 μg folate-6-5-methyltetrahydrofolate, 3 mg vitamin B6, 5 μg vitamin B12, 2.4 mg vitamin B2, 12.5 mg zinc and 250 mg betaine (Normocis(400®)) once daily for two months, or supplementation with highly dosed folic acid (5 mg/day) (control group). Differences in serum HCys values were compared by ANOVA for repeated measures. A significant HCys reduction in comparison to baseline was found in both groups at the end of the study treatment, from 21.5±8.7 to 10.0±1.7 μmol/L for Normocis(400®) subjects (p less than 0.0001), and from 22.6±6.2 to 14.3±2.8 μmol/L for controls (p less than 0.0001). HCys reduction was significantly higher among patients treated with Normocis(400®) (p less than 0.035). The ideal HCys level (i.e. less than 10 μmol/L) was reached in 55.8% of cases in theNormocis(400®) group, and it was significantly higher than in controls. No side effects were observed in either treatment group. Randomized clinical trials are ongoing to test the effect of folate, B6, and B12 supplementation in primary prevention of cardiovascular and cerebrovascular events. In the meantime, especially when the ideal HCys level is far from being reached, Normocis(400®) appears to be safe, well tolerated and effective in reducing HCys levels.
  7. McBreairty et al.: Betaine is as effective as folate at re-synthesizing methionine for protein synthesis during moderate methionine deficiency in piglets. Eur J Nutr 2016;55:2423-2430. PMID: 26419586. DOI. PURPOSE: Both folate and betaine (synthesized from choline) are nutrients used to methylate homocysteine to reform the amino acid methionine following donation of its methyl group; however, it is unclear whether both remethylation pathways are of equal importance during the neonatal period when remethylation rates are high. Methionine is an indispensable amino acid that is in high demand in neonates not only for protein synthesis, but is also particularly important for transmethylation reactions, such as creatine and phosphatidylcholine synthesis. The objective of this study was to determine whether supplementation with folate, betaine, or a combination of both can equally re-synthesize methionine for protein synthesis when dietary methionine is limiting. METHODS: Piglets were fed a low methionine diet devoid of folate, choline, and betaine, and on day 6, piglets were supplemented with either folate, betaine, or folate + betaine (n = 6 per treatment) until day 10. [1-(13)C]-phenylalanine oxidation was measured as an indicator of methionine availability for protein synthesis both before and after 2 days of supplementation. RESULTS: Prior to supplementation, piglets had lower concentrations of plasma folate, betaine, and choline compared to baseline with no change in homocysteine. Post-supplementation, phenylalanine oxidation levels were 20-46 % lower with any methyl donor supplementation (P = 0.006) with no difference among different supplementation groups. Furthermore, both methyl donors led to similarly lower concentrations of homocysteine following supplementation (P < 0.05). CONCLUSIONS: These data demonstrate an equal capacity for betaine and folate to remethylate methionine for protein synthesis, as indicated by lower phenylalanine oxidation.
  8. Kunisawa et al.: Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex. Behav. Brain Res. 2015;292:36-43. PMID: 26057356. DOI. Betaine plays important roles that include acting as a methyl donor and converting homocysteine (Hcy) to methionine. Elevated plasma Hcy levels are known as hyperhomocysteinemia (HHcy) and contribute to impairments of learning and memory. Although it is commonly known that betaine plays an important role in Hcy metabolism, the effects of betaine on Hcy-induced memory impairment have not been investigated. Previously, we demonstrated the beneficial effects of betaine on acute stress and lipopolysaccharide-induced memory impairment. In the present study, we investigated whether betaine ameliorates Hcy-induced memory impairment and the underlying mechanisms of this putative effect. Mice were treated with Hcy (0.162mg/kg, s.c.) twice a day for nine days, and betaine (25mg/kg, s.c.) was administered 30min before the Hcy injections. The memory functions were evaluated using a spontaneous alternation performance test (Y-maze) at seven days and a step-down type passive avoidance test (SD) at nine and ten days after Hcy injection. We found that betaine suppressed the memory impairment induced by repeated Hcy injections. However, the blood concentrations of Hcy were significantly increased in the Hcy-treated mice immediately after the passive avoidance test, and betaine did not prevent this increase. Furthermore, Hcy induces redox stress in part by activating matrix metalloproteinase-9 (MMP-9), which leads to BBB dysfunction. Therefore, we tested whether betaine affected MMP-9 activity. Interestingly, treatment with betaine significantly inhibited Hcy-induced MMP-9 activity in the frontal cortex but not in the hippocampus after acute Hcy injection. These results suggest that the changes in MMP-9 activity after betaine treatment might have been partially responsible for the amelioration of the memory deficits and that MMP-9 might be a candidate therapeutic target for HHcy.
  9. Alirezaei et al.: Beneficial antioxidant properties of betaine against oxidative stress mediated by levodopa/benserazide in the brain of rats. J Physiol Sci 2015;65:243-52. PMID: 25665954. DOI. UNLABELLED: The present study was designed to evaluate antioxidant effects of betaine in the brain following administration of levodopa and benserazide, which are routinely used in the treatment of Parkinson's disease. Sprague-Dawley male rats were divided into levodopa (LD), Betaine (Bet.), levodopa plus betaine (LD/Bet.), levodopa plus benserazide (LD/Ben.), levodopa plus betaine-benserazide (LD/Bet.-Ben.) and control groups. The experimental groups received LD 300 mg/kg, Bet. 1.5 % w/w of the total diet, Ben. 75 mg/kg and distilled water to controls for 10 consecutive days, orally. The concentration of plasma total homocysteine significantly increased in LD/Ben.-treated rats when compared to the other groups. Brain glutathione peroxidase (GPx) activity and glutathione content both elevated with betaine treatment in LD/Bet. and LD/Bet.-Ben groups. Superoxide dismutase activity was also higher in controls and betaine-treated rats in comparison with LD and LD/Ben. groups. Likewise, catalase activity significantly increased in control and betaine groups when compared to LD- and LD/Ben.-treated rats. In contrast, brain lipid peroxidation significantly increased in response to LD and LD/Ben. TREATMENTS: Regarding metabolism of LD in peripheral tissues, serumic dopamine concentration significantly increased in LD-treated rats in comparison with LD/Ben. group. The present results show beneficial antioxidant and methyl donor properties of betaine versus oxidative stress and hyperhomocysteinemia induced by levodopa and benserazide in an animal model.