Magnesium Threonate

Discussion in 'Magnesium' started by hiconscience, Jan 2, 2020.

  1. hiconscience

    hiconscience Member

    Joined:
    May 10, 2017
    Messages:
    116
    Gender:
    Female
    Location:
    USA
  2. homyak

    homyak Member

    Joined:
    Sep 8, 2019
    Messages:
    27
    Gender:
    Male
    I've been experimenting with different types of magnesium for years now, but I still think that topical application of Idealab's Magnoil is the best. High quality Magnesium Threonate is not worth the price.
     
  3. Opioidus

    Opioidus Member

    Joined:
    May 22, 2019
    Messages:
    80
    Gender:
    Male
    I have a bottle of Magnesium Threonate and it's the biggest meme out there! As far as regular Magnesium benefits go it only improves my sleep slightly, magnesium citrate is much better for anxiety or muscle relaxation. I love scented Epsom salts and use them every time I take a bath, much better for mood than any oral supplements.
     
  4. Momentum

    Momentum Member

    Joined:
    Dec 9, 2019
    Messages:
    84
    Gender:
    Female
    Spent the money, took it for two months and noticed nothing :-(
     
  5. jb116

    jb116 Member

    Joined:
    Jun 29, 2015
    Messages:
    911
    Gender:
    Male
    Location:
    NJ
    I had asked Ray about this a couple of years ago and he believes that it's mostly marketing, in regards to it "getting into the brain easier" because he said all magnesium gets into the brain easily. But the reason I had asked is because without fail, when I had taken this form of magnesium, I had deep, vivid dreams and at the same time restful sleep. It happened every single time. So, I don't know, but at least it's not harmful to take. If you get benefit from it too, use it.
     
  6. Max23

    Max23 Member

    Joined:
    Jun 11, 2018
    Messages:
    171
    Gender:
    Male
    I am quite disappointed with this product. It produces no effects. Slightly increases my tinnitus.
     
  7. GenericName86

    GenericName86 Member

    Joined:
    Jun 30, 2018
    Messages:
    29
    Gender:
    Male
    I used it briefly and actually noticed benefits only a few hours after supplementation. While it didn't really do anything for my anxiety my mental imaging and imagination become way clearer, like if i was just sitting down and daydreaming everything was so clear like i was actually there. I went onto the nootropics subreddit to read further experiences and one of things i read that put me off it was that while yes, it does help "repair" the brain, once you stop taking it you pretty much go back to baseline as your brain can't support the growth it experienced while supplementing it after you discontinue. No idea if that's true but it put me off it.

    I'm actually wondering if one of the reasons i saw benefits if because my brain is damaged in some way and why some people say they didn't notice anything.
     
  8. Homo Consumericus

    Homo Consumericus Member

    Joined:
    Dec 8, 2018
    Messages:
    383
    Gender:
    Male
    Location:
    The Netherlands
    Less than 10% of magnesium threonate is magnesium (at least in the formulations I've come across) so you would really be supplementing a [edit: sugar acid] rather than a mineral. I feel the same way about all the forms of magnesium bound to an amino acid-- what one experiences is primarily due to the amino rather than the magnesium.

    Regarding amino acid chelated minerals, there are more efficient ways of getting magnesium into the body, and there are forms of magnesium unbound to amino acids which do not induce heavy manipulation of one's mental disposition.
     
  9. High_Prob

    High_Prob Member

    Joined:
    Mar 23, 2016
    Messages:
    275
    Gender:
    Male
    Threonate is Threonic Acid which is a sugar acid not an amino acid. Threonine is an amino acid but it’s not the same as Threonate (Threonic Acid)...
     
  10. Homo Consumericus

    Homo Consumericus Member

    Joined:
    Dec 8, 2018
    Messages:
    383
    Gender:
    Male
    Location:
    The Netherlands
    Thanks for pointing out.
     
  11. High_Prob

    High_Prob Member

    Joined:
    Mar 23, 2016
    Messages:
    275
    Gender:
    Male
    Here is a more detailed explanation by Travis:


     
  12. Homo Consumericus

    Homo Consumericus Member

    Joined:
    Dec 8, 2018
    Messages:
    383
    Gender:
    Male
    Location:
    The Netherlands
    Thank you once again.

    I spent some time yesterday trying to find information on the similarities and differences between threonic acid and threonine and immediately found a half dozen websites which had incorrectly defined threonate, so Travis' explanation is much appreciated.

    (Off topic, his final bit about arginine seems to make a solid case for limiting gelatin as a source of glycine in favour of isolated glycine.)
     
  13. High_Prob

    High_Prob Member

    Joined:
    Mar 23, 2016
    Messages:
    275
    Gender:
    Male
    OpenAthens / Sign in

    Regulation of structural and functional synapse density by L-threonate through modulation of intraneuronal magnesium concentration

    Highlights



    Threonate concentrations in rat CSF is approximately 100 μM, approximately 5-fold higher than blood plasma concentrations.


    Oral treatment with L-TAMS selectively increases CNS threonate by 50%, with no peripheral accumulation of threonate.


    Threonate increases neuronal [Mg2+]i, and augments structural and functional synapse density.


    Threonate-induced increase of [Mg2+]i and downstream functional synapse density was specifically mediated through GLUTs.


    Threonate enhances the expression of Syn and PSD-95 in human neural stem cell-derived neurons.




    Abstract
    Oral administration of the combination of L-threonate (threonate) and magnesium (Mg2+) in the form of L-Threonic acid Magnesium salt (L-TAMS) can enhance learning and memory in young rats and prevent memory decline in aging rats and in Alzheimer’s disease model mice. Recent results from a human clinical trial demonstrate the efficacy of L-TAMS in restoring global cognitive abilities of older adults. Previously, we reported that neuronal intracellular Mg2+ serves as a critical signaling molecule for controlling synapse density, a key factor that determines cognitive ability. The elevation of brain Mg2+ by oral administration of L-TAMS in intact animals plays a significant role in mediating the therapeutic effects of L-TAMS. The current study sought to elucidate the unique role of threonate. We aimed to understand if threonate acts directly to elevate intraneuronal Mg2+, and why Mg2+ given without threonate is ineffective for enhancing learning and memory ability. We discovered that threonate is naturally present in cerebrospinal fluid (CSF) and oral treatment with L-TAMS elevated CSF threonate. In cultured hippocampal neurons, threonate treatment directly induced an increase in intracellular Mg2+ concentration. Functionally, elevating threonate upregulated expression of NR2B-containing NMDAR, boosted mitochondrial membrane potential (ΔΨm), and increased functional synapse density in neuronal cultures. These effects are unique to threonate, as other common Mg2+ anions failed to have the same results. Mechanistically, threonate’s effects were specifically mediated through glucose transporters (GLUTs). We also evaluated the effects of threonate in human neural stem cell-derived neurons, and found it was equally effective at upregulating synapse density. The current study provides an explanation for why threonate is an essential component of L-TAMS and supports the use of L-TAMS to promote cognitive abilities in human.


    1. Introduction
    L-Threonate, (2R,3S)-2,3,4-Trihydroxybutanoate, is a naturally occurring sugar acid present in the body, with the structure C4H7O5. It has been found in the periphery in plasma and the aqueous humor of the eye (Deutsch et al., 1999, Harding et al., 1999). How threonate is eliminated from the body is not fully understood; however, so far we know that approximately 10% is excreted in urine (Lawson et al., 1976, Thompson et al., 1975, Wang et al., 2011).

    Recent studies show that threonate might have a physiological function. In the periphery, threonate has been linked to bone health. Threonate can prevent bone degradation by inhibiting osteoclast resorption from bone (He et al., 2005). Threonate also supports bone formation in two ways. One, it promotes calcium bioavailability, allowing for rapid absorption of calcium into the body (Wang et al., 2013). Two, threonate increases bone mineralization by inhibiting DHT-inducible dickkoppf-1 (DKK-1) expression. DKK-1 is an osteoblast inhibitory factor whose overexpression can negatively impact bone formation and density (Kwack et al., 2008, Kwack et al., 2010, Monroe et al., 2012).

    Our previous work showed that threonate also has effects in the central nervous system (CNS). Oral treatment with the combination of threonate and magnesium (Mg2+) in the form of L-threonic acid Magnesium salt (L-TAMS) increases synapse density and memory ability in both aged rats and late stage Alzheimer’s disease (AD) model mice (Li et al., 2014, Slutsky et al., 2010). A recent study shows that L-TAMS is also effective at improving cognitive deficits in humans (Liu et al., 2015).

    Cognitive decline is best correlated with brain atrophy associated with synaptic loss (Jack et al., 2015, Ridha et al., 2006, Terry et al., 1991). In fact, alteration of synaptic efficacy in the hippocampus is an initial event in cognitive disorders such as AD (Selkoe, 2002). Considering synapses are the elemental unit of neural computation, it is not surprising that the both the physical loss of synapses (reduced structural density) and the loss of function among the remaining synapses (reduced functional synapse density) are associated with impaired cognition. Notably, we have demonstrated that neuronal intracellular Mg2+ concentration [Mg2+] is a critical signaling molecule regulating structural and functional terminal density, with higher intracellular [Mg2+] resulting in greater structural and functional terminal density (Zhou and Liu, 2015).

    Our work has shown that not only does neuronal intracellular Mg2+ promote structural synapse density and plasticity, but it also controls whether presynaptic terminals are functional or nonfunctional (Zhou and Liu, 2015). Functional synapses are able to release neurotransmitter containing vesicles and thus affect the post-synaptic neuron, while nonfunctional synapses are structurally present but fail to release neurotransmitter and are unable to signal to the post-synaptic neuron.

    Threonate is a critical component of L-TAMS; when animals are treated with Mg2+ that is not coupled to threonate (ie. an alternate anion such as chloride is used), there is no significant effect on memory ability (Slutsky et al., 2010). However, threonate treatment alone, without Mg2+, also does not affect memory ability, suggesting that there is a synergistic effect between threonate and Mg2+ (Slutsky et al., 2010).

    While L-TAMS has been shown to be effective at improving cognition, there are still unanswered questions about the unique role of threonate and why L-TAMS treatment is effective at improving learning and memory ability but Mg2+ treatment in the absence of threonate is not. These questions were examined in the current study. Specifically, we investigated if there is uptake of threonate into the CNS following oral treatment with L-TAMS, and if threonate itself has any effects on hippocampal neurons. Because threonate and Mg2+ are both required for effects on cognition in an intact animal, we explored their interaction, focusing on how threonate affects Mg2+ homeostasis in the neuron, and functional/structural synapse density. Finally, and perhaps most importantly, we asked whether threonate is naturally present in the CNS and if it has any physiological functions.

    4. Discussion
    Threonate is an endogenous small molecule shown to have a possible physiological function in the periphery - supporting bone health. However, until now, there have been no reports of the presence of or a physiological role for threonate in the CNS. In the current study, we showed for first time that threonate is present in the rat CSF and human CSF (data not shown), surprisingly at an approximate 5-fold higher concentration than in the periphery. We identified threonate as a unique molecule that can efficiently regulate structural and functional synaptic density in the CNS. Here we show that threonate treatment of hippocampal neuronal cultures increased mitochondrial function, proteins critical for synaptic plasticity, and structural and functional synapse density, in a dose-dependent manner. Importantly, we also identified the likely signaling mechanism by which threonate affects functional synapse density. We show that threonate elevates neuronal intracellular [Mg2+], which acts as a “second messenger” for threonate in regulating synapse density (Zhou and Liu, 2015).

    We have carried out experiments to decipher the possible mechanism underlying the elevation of neuronal intracellular [Mg2+] by threonate, which could be due to increased Mg2+ influx or decreased Mg2+ efflux. We observed that when we dropped extracellular [Mg2+] to 0.1 mM in an attempt to reduce the driving force for Mg2+ influx, threonate treatment no longer elevated intracellular [Mg2+]. These results are most compatible with the interpretation that threonate promotes Mg2+ influx.

    We conducted several experiments to identify the possible channel responsible for threonate-mediated Mg2+ influx into neurons. The candidates we considered were channels that have high potential to transport threonate, including GLUTs and SVCT2, based on threonate’s structure and related chemical precursors. Threonate is formed by the spontaneous conversion of the ascorbic acid oxidation product dehydroascorbic acid (DHA) into oxalic acid and threonic acid (Kallner et al., 1985, Thornalley, 1998). GLUTs have specificity for the threonate precursor DHA and is also known to transport monosaccharides and other small carbon compounds via passive facilitated transport, whereas SVCT2 has specificity for ascorbic acid (Augustin, 2010, Rumsey et al., 1999). Blocking GLUTs, but not SVCT2, suppressed both threonate-mediated Mg2+ influx and increase of functional synaptic density. Although the CB experiments suggest that GLUTs are responsible for threonate-mediated influx of Mg2+ into neurons, since the specificity of CB to GLUTs cannot be completely confirmed, additional experiments, such as siRNA knock-down, are required before we can conclusively conclude that it is GLUTs that mediate the action of threonate on intracellular Mg2+ concentration. Nevertheless, given the chemical structure similarity between DHA and threonate, we speculate that GLUTs facilitate threonate transport into the cell while co-transporting Mg2+.

    Because the drug we used to block GLUTs is not specific for a particular GLUT, we do not know which of the GLUTs expressed in the brain (GLUTs 1–4, 6, 8, 10, 13) are capable of threonate-mediated transport of Mg2+ into neurons. Although, among the brain expressed GLUTs, GluTs 1 and 3 are known to transport DHA, suggesting that they might also be responsible for threonate transport (Rumsey et al., 1997). GluT3, but not GluT1, is highly constitutively expressed on hippocampal neurons as the primary mediator of neuronal glucose uptake (Leino et al., 1997, Maher et al., 1991, Nagamatsu et al., 1992, Vannucci et al., 1997). Therefore, threonate-induced transport of Mg2+ into hippocampal neurons likely occurred primarily through GluT3 in our experiments. Interestingly, GluT1 is highly expressed on endothelial cells of the blood brain barrier, important for glucose uptake into the brain (Koranyi et al., 1991, Simpson et al., 2001, Yeh et al., 2008). Therefore, GluT1 may be responsible for the observed threonate-mediated transport of Mg2+ into the brain (Slutsky et al., 2010).

    Maintaining a sufficient amount of synapses is essential for brain function. Indeed, the decline of cognitive function during aging is strongly correlated with the degree of synapse loss (Morrison and Baxter, 2012). Identifying the endogenous molecule that regulates synapse density will likely be of broad significance. So far, only a handful of endogenous molecules have been shown to have a role in upregulating synapse density. For example, estrogen can efficiently increase synapse density in hippocampal neurons (Mukai et al., 2010). Acetyl-l-carnitine (ACL), a derivative of the constitutively expressed fatty acid transporter L-carnitine, can potentially promote hippocampal dendritic spine density (Kocsis et al., 2014). The current study shows that threonate might be an important constitutively present molecule in the CSF required for maintaining high synapse density.

    Translationally, a threonate or Mg2+ compound might be useful to increase synapse density and promote learning and memory. Surprisingly, in our previous animal experiments, we found that treatment with either threonate or Mg2+ but without the other was ineffective (Slutsky et al., 2010). Only treatment with the combination of threonate and Mg2+ as a single compound can elevate memory ability. While oral treatment with threonate and Mg2+ (in the form of L-TAMS) can efficiently increase synapse density and memory ability in both aged rats and late stage AD model mice (Li et al., 2014, Slutsky et al., 2010), threonate treatment without Mg2+ (in the form of NaT) and Mg2+ treatment without threonate (in the form of Mg2+-chloride, -citrate, -glycinate, and –gluconate) fails to increase short- or long-term memory ability (Slutsky et al., 2010).

    If threonate is effective in increasing intraneuronal Mg2+ and synapse density in cultured hippocampal neurons, it is curious why it does not have an effect in the intact animal. One possible explanation is that threonate might not be able to promote Mg2+ influx into neurons without a simultaneous increase of extracellular brain Mg2+ supply. This is because Mg2+ as a signaling molecule is unique in that the majority of Mg2+ is stored inside the cell and there is a relatively very small amount of Mg2+ in the extracellular space. Therefore, a large influx of Mg2+ can lead to a significant reduction of extracellular Mg2+, thereby reducing the driving force of Mg2+, preventing further influx. This phenomenon can be observed with insulin treatment. Insulin promotes Mg2+ influx into the cell, significantly reducing extracellular Mg2+. For example, plasma Mg2+ levels initially decrease significantly following an insulin injection, but can be prevented when insulin is injected with Mg2+ supplementation, such as from a meal (Paolisso et al., 1986). Since the amount of total extracellular brain Mg2+ is low (Ramadan et al., 1989), threonate treatment without concurrent Mg2+ treatment, like with insulin treatment, could quickly reduce CSF Mg2+, resulting in a reduction of the driving force for all Mg2+ channels, limiting the amount of Mg2+ influx that threonate can promote. This might explain why threonate treatment alone does not work in vivo, whereas in culture, where the extracellular [Mg2+] is essentially clamped, threonate treatment effectively increases intracellular [Mg2+].

    Similar to the effects of increasing CSF threonate without increasing Mg2+, increasing CSF Mg2+ without increasing CSF threonate will also not be effective. One cannot limitlessly elevate extracellular brain Mg2+ in order to elevate intracellular [Mg2+], as the relationship between extracellular and intracellular [Mg2+], and the relationship of extracellular [Mg2+] and synapse density are bell-shaped. As shown in Fig. 2 and Fig. 5, when the extracellular [Mg2+] is increased beyond 0.8 mM, intracellular [Mg2+] and synapse density decreased.

    The greatest increase in vitro of intracellular [Mg2+] and functional synapse density occurred with the concurrent increase of threonate and extracellular [Mg2+] (Fig. 2, Fig. 5A, B). In vivo, threonate and Mg2+ oral treatment (L-TAMS) increased brain threonate by approximately 50% (Fig. 1C) and CSF Mg2+ by approximately 15%, leading to an increase of synapse density by as much as 67% (Slutsky et al., 2010). The current study provides more mechanistic insight into the therapeutic potential of L-TAMS for cognitive impairment. A recent double-blinded placebo-controlled clinical study showed promise for L-TAMS in treating cognitive impairment in humans (Liu et al., 2015).
     
Loading...