Time to Cut Glycine from my Stack? (this would include GlyNAC)

[Bolt_Upright]

So I was perusing the Rhyothemis blog rhyobrain.blogspot.com and stumbled across something concerning "Hcy neurological harm depends on glycine levels" rhyobrain.blogspot.com/2021... which led me to this:

The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice 2019 ncbi.nlm.nih.gov/pmc/articl...

"The mechanism of damage evoked for Hcy excitatory role has been found [65,66]: Hcy is an agonist of the endogenous glutamate receptors, NMDA receptors [67,68].

Through Hcy-NMDA binding, Hcy indirectly enhances calcium influx [69]. This is not a constant reaction, and it largely depends in the Glycine concentration; when glycine is in normal concentration (10 μmol/L), Hcy acts as a partial antagonist of the glycine site of the NMDA receptor, and it inhibits the receptor-mediated activity, acting as a neuroprotective factor [23,65]. Therefore, it can be easily demonstrated that when glycine levels are normal, only HHcy could exert a toxic effect (i.e., Hcy = 100 μmol/L).

On the contrary, when glycine levels are higher inside the brain, more than 10 μmol/L, (and this occurs in clinical conditions in different scenario: brain ischemia, head trauma, or even protracted migraine cluster), even a low concentration of Hcy (i.e., Hcy = 10 μmol/L) could be an agonist on NMDA [70,71], exerting an excitatory action, and enhancing calcium influx.

More recent data underlies a new possible mechanism of Hcy’s action: its direct activation of the group I metabotropic glutamate receptors, by competing with inhibitory neurotransmitters, such as GABA [70], inducing also this way an increase of calcium influx. "

I am trying to lower my Homocysteine levels, not add things to my brain that make Homocysteine more successful at damaging my brain.

For now, Glycine is off the stack. Please explain why I am mistaken.

Update: windhorsepixy provided some good counterpoint (and made me remember how well I have been sleeping):

Glycine, the smallest amino acid, confers neuroprotection against d-galactose-induced neurodegeneration and memory impairment by regulating c-Jun N-terminal kinase in the mouse brain 2020 jneuroinflammation.biomedce...

Wow: Conclusion

Our findings demonstrate that Gly-mediated deactivation of the JNK signaling pathway underlies the neuroprotective effect of Gly, which reverses d-gal-induced oxidative stress, apoptotic neurodegeneration, neuroinflammation, synaptic dysfunction, and memory impairment. Therefore, we suggest that Gly (an amino acid) is a safe and promising neurotherapeutic candidate that might be used for age-related neurodegenerative diseases.

Thank you windhorsepixy ! I was really hoping somebody would steer me back to Glycine. You may have done it!

[Bolt_Upright]

This article from 1997 seems to say the same thing: Neurotoxicity associated with dual actions of homocysteine at theN-methyl-D-aspartate receptor pnas.org/content/pnas/94/11...

[Hidden]

Bolt, if you are looking for something to research, you might want to shelve glycine for now at least.

I will again mention (I think I’m being redundant as I’m prone to being) TUDCA.

It is a bile acid with a long history that is very widely used and there is evidence to support its use.

Btw:

UDCA + taurine = or results in TUDCA.

Cure Parkinson’s is trialing UDCA

[Bolt_Upright in reply to Hidden]

Thanks CC! For the record, Glycine is off my list.

I have some Tudca and am happy to add it back to my list.

Tudca is god for the gut. The gut is my focus area.

[Bolt_Upright in reply to Bolt_Upright]

Tauroursodeoxycholic acid (TUDCA) is neuroprotective in a chronic mouse model of Parkinson's disease 2020 pubmed.ncbi.nlm.nih.gov/333...

[Bolt_Upright in reply to Hidden]

Tauroursodeoxycholic Acid Improves Motor Symptoms in a Mouse Model of Parkinson's Disease 2018 pubmed.ncbi.nlm.nih.gov/296...

[Hidden in reply to Bolt_Upright]

University of Sheffield has good info “UDCA rescues mitochondrial function in common forms of familial PD.”

Trial is using 2,250 - 2,250 mg a day

[Bolt_Upright in reply to Hidden]

researchgate.net/publicatio...

[Smittybear7 in reply to Bolt_Upright]

Does it stop tremors

[Bolt_Upright in reply to Smittybear7]

Does TUDCA stop tremors? I don't know. I had never heard it offered any symptomatic relief, but really, I don't know.

[Smittybear7 in reply to Bolt_Upright]

Thank you

[Hidden in reply to Smittybear7]

Go ….. To ……. The ……Root……..Causes

Tremors are a result of the PD pathology not the cause.

TUDCA, does it stop tremors, No, not directly.

Is it very beneficial from an upstream perspective?

Based on the abundance of data on it, yes, I believe it is.

We deserve and need more than bandaids!

Looking for immediate symptomatic relief is putting a bandaid in the wound.

A supplement like TUDCA addresses the cause of the wound.

edit: if that was feisty or rude I really did not mean to be! I just want so much for all PWP to address the root causes and collectively get better in addition to addressing symptoms. ❤️

[Bolt_Upright]

TUDCA in the Treatment of Prion Disease maes.umn.edu/seelig67-018 (some people think PD is a prion disease)

[LAJ12345]

Restore gold has tudca in it

[Bolt_Upright]

I started a new TUDCA/UDCA thread healthunlocked.com/cure-par...

(just in case anybody wants to post about Glycine on this thread)

[windhorsepixy]

I choose to give MY attention to this instead : (to each his own poison or cure) -

michaeljfox.org/grant/glyci...

and

jneuroinflammation.biomedce...

My hwp (w/REM Sleep Disorder) & I actually have sound, uninterrupted sleep for the 1st time in years with Glycine (1 g.) (After trying literally everything else). I intend to take it for the rest of my life as I wake up feeling alive - instead of the living dead. Sleep deprivation takes it's own toll in myriad maladies.

[Bolt_Upright in reply to windhorsepixy]

Good point! You know, my REMSBD has been practically gone since I started the Glycine!

I checked out the MJF page. "Glycine Uptake Inhibitors as Potential Enhancers of Dopaminergic Axon Regeneration" so I Googled and found:A glycine reuptake inhibitor (GRI) is a type of drug which inhibits the reuptake of the neurotransmitter glycine by blocking one or more of the glycine transporters (GlyTs).

Checked out the journal: "Glycine, the smallest amino acid, confers neuroprotection against d-galactose-induced neurodegeneration and memory impairment by regulating c-Jun N-terminal kinase in the mouse brain".

Wow: Conclusion

Our findings demonstrate that Gly-mediated deactivation of the JNK signaling pathway underlies the neuroprotective effect of Gly, which reverses d-gal-induced oxidative stress, apoptotic neurodegeneration, neuroinflammation, synaptic dysfunction, and memory impairment. Therefore, we suggest that Gly (an amino acid) is a safe and promising neurotherapeutic candidate that might be used for age-related neurodegenerative diseases.

Thank you windhorsepixy ! I was really hoping somebody would steer me back to Glycine. You may have done it!

[Oceanwind in reply to windhorsepixy]

I just saw a YouTube video with Eric Berg discussing how glycine increases your serotonin. I’ve had restless leg syndrome for the last two years and my sleep is harder to get so I’m going to try a glycine supplement.

[Bolt_Upright]

Now this one kind of bothers me: "Glycine Uptake Inhibitors as Potential Enhancers of Dopaminergic Axon Regeneration" michaeljfox.org/grant/glyci...

so I Googled and found:A glycine reuptake inhibitor (GRI) is a type of drug which inhibits the reuptake of the neurotransmitter glycine by blocking one or more of the glycine transporters (GlyTs).

This seems to be the oposite of taking Glycine (I have a HS Education):

We have found that glycine uptake inhibitors that enhance NMDA glutamate receptor activity promote striatal dopaminergic re-innervation in a toxin-based pre-clinical model of Parkinson’s disease. Adult mice received unilateral intrastriatal 6-OHDA injections. Three weeks after the lesion the dorsal striatum was devoid of dopamine neurites. After an additional four weeks, a gradual and partial dopaminergic re-innervation of the dorsal striatum occurred in untreated mice. This re-innervation was enhanced by 30% when mice were treated with a glycine uptake inhibitor beginning three weeks after the lesion. Dopamine release recordings indicated that this recovery was also functional. Thus, glycine uptake inhibitors promote functional dopaminergic sprouting, a finding that we think should be carefully examined as a new avenue for therapy development for Parkinson’s disease.

[Rhyothemis in reply to Bolt_Upright]

It probably goes in the same direction - increasing extracellular glycine levels in brain making it more available for receptors on the surface of neurons. Though I wonder what effect that has on red blood cells, since glycine is needed for heme synthesis and I think it is the same transporter on RBCs. I also wonder about what if any effect a glycine transport inhibitor would have on glycine transport into the CSF (cerebrospinal fluid) from the blood.

Note that one MSA case that had a glycine transporter mutation. (but MSA is not PD and that was one case - unfortunately no follow up on that topic as far as I can see in the literature ... ) pubmed.ncbi.nlm.nih.gov/982...

[Rhyothemis in reply to Rhyothemis]

RBCs have GlyT1

astrocytes have GlyT1

neurons of the spinal cord, brain stem and cerebellum (regions affected by MSA) have GlyT2

haematologica.org/article/v...

frontiersin.org/articles/10...

pubmed.ncbi.nlm.nih.gov/938...

[Rhyothemis in reply to Rhyothemis]

just wanted to jot down a thought before I forget it - if glycine is needed for heme for hemoglobin in RBCs, is it needed for CBS synthesis in other cell types? (heme is in other things besides hemoglobin)

[Bolt_Upright in reply to Rhyothemis]

2 days later and I am still trying to figure out what "glycine uptake inhibitors" do.

starting to think that, like SSRIs, glycine uptake inhibitors actually increase the level of Glycine in the brain.

frontiersin.org/articles/10...

An alternative approach to increase glycine availability is to block glycine reuptake via GlyT1. However, even though several GlyT1 inhibitors seemed to be efficacious in animal models, clinical studies in humans have been disappointing at least for major endpoints. The most advanced compound tested with the highest accuracy in terms of sample size and duration of the trials, is the non-competitive GlyT1 antagonist bitopertin, which also failed to reach its endpoints in Phase III trials.

[windhorsepixy]

Still - I really value having actual restful sleep. I am incredibly grateful for it for that alone. Diphenhydramine is being pushed on the general public as a “Sleep Aid” - even in mass in the dollar stores. It (& other anticholinergic drugs) are totally being linked to contributing to dementia. It’s really unconscionable. health.harvard.edu/blog/com...

[Bolt_Upright in reply to windhorsepixy]

Yikes!

[jeffmayer]

English would be nice

[jocelyng in reply to jeffmayer]

I’m with you there. I need someone to say:

Take this at this dosage at this time of day and buy it here.

I haven’t had my coffee yet, but I honestly don’t think it would matter.

[Bolt_Upright in reply to jocelyng]

Sorry about that jocelyng. We are debating whether Glycine is beneficial for PD or actually might make PD worse. Glycine is very popular and I was taking it with NAC. It is very popular to combine the 2. They sell GlyNAC powder. I have read reports of how they work together well. But then I saw that story that homocisteine neurological harm depends on glycine levels. Without the glycine the homocisteine can only do a fraction of the damage. And here I am adding glycine to my brain. That is a quandary and there is probably no authority that really knows if taking glycine is helpful or detrimental. So it's a coin toss as far as I am concerned now (which puts it off my stack).

I should add: I have a HS degree. I am not an authority.

[Bolt_Upright in reply to jocelyng]

I do think B3 is worth considering: healthunlocked.com/cure-par...

[Bolt_Upright in reply to jeffmayer]

Sorry about that Jeff. We are debating whether Glycine is beneficial for PD or actually might make PD worse. Glycine is very popular and I was taking it with NAC. It is very popular to combine the 2. They sell GlyNAC powder. I have read reports of how they work together well. But then I saw that story that homocisteine neurological harm depends on glycine levels. Without the glycine the homocisteine can only do a fraction of the damage. And here I am adding glycine to my brain. That is a quandary and there is probably no authority that really knows if taking glycine is helpful or detrimental. So it's a coin toss as far as I am concerned now (which puts it off my stack).

I should add: I have a HS degree. I am not an authority.

[Rhyothemis]

Unfortunately what we really need is a human trial specifically for PD - as well as (and especially) for MSA and LBD - and as usual that does not seem to be a priority.

Glycine has been found to extend life in animal models. NAC on the other hand reduced lifespan in nematode worms, not sure about mice. Also have not checked if combination has been tested for lifespan effects.

But in ppl w/ MSA (and maybe LBD) it seems to surge in CSF after ingestion. Personally the relaxation effect I get from glycine is a bit disconcerting - it means I have seriously jacked up my brain levels. Is that overall good or bad in the long term? - I don't know. I have more notes on glycine here: rhyobrain.blogspot.com/2020...

OTOH many people have taken gelatin and now collagen supplements as a sleep aid for many, many years and if there were harms you'd think we would have heard about them by now. Collagen peptides have a lot of interesting properties & have a lot of glycine; uptake of glycine might be a bit slower than when taking as a free amino acid. There are issues to consider with collagen, just like everything else - possibility of BMAA in marine collagen; BSE, Neu5Gc in beef/pork collagen.

I think taking glycine when having a headache should probably be avoided.

~

OT: I think I may be messing up by taking a bunch of flax for fibrocystic breast. My brain is not doing too well on it. Flax is supposed to be great for everything - but it works in similar way to tamoxifen: movementdisorders.onlinelib...

breast health or brain health - which one do I choose?

[Bolt_Upright in reply to Rhyothemis]

Dr Google says fibrocystic breast is benign. I'd choose the brain health.

[Rebtar in reply to Rhyothemis]

Are you post menopausal? My understanding is that fibrocystic breasts are not a problem and my experience is that they become less dense after menopause (mine did). I didn't, however, have a LOT of density.

[Rhyothemis in reply to Rebtar]

I just stopped getting my periods about 2 or 3 months ago, pretty sure this is it since my usual tricks for getting them back have not worked (fish oil, green legumes, niacin).

My first bout of fibrocystic breast (FB) came a couple of weeks after a mammogram where they zapped me three times on the left since it was very dense; the left side blew up like a balloon and I thought I might have inflammatory breast cancer. The right side was fine symptom-wise but ultrasound found some cysts there as well. The difference between them was the number of X-rays. That whole thing put me off mammography - I decided I would wait until 50 to get regular mammograms (based on the Malmo study). I'm 53 and have put it off due to my daughter's illness and then the pandemic.

I need topical estrogen though for vulvar vestibulitis and LUTS (I find it helps to just put it on the urethral opening - estrogen is neurotrophic - don't know how, the effect seems to travel up the nerves), but I think they won't do the refill Rx until I get a mammogram.

FB might be benign but it is associated with increased breast cancer (BC) risk and I find it very painful. Which is odd since mastalgia is associated with lower risk of BC (I would like to ask an expert about that apparent paradox).

It seems to be clearing up so I can back off a bit, but the flax really brings down the density and I want to reduce density as much as possible before getting 'zapped' again - so they only do it once per side.

[Rebtar in reply to Rhyothemis]

Good for you, finding how to take care of that.

[Bolt_Upright in reply to Rhyothemis]

Thanks for the blog post. Looks like Glycine is off my stack.

[Rhyothemis in reply to Bolt_Upright]

I hope you won't be mad at me if a couple of years from now they find out it benefits most ppl w/ Parkinsons.

There really should be clinical trials - many ppl are taking glycine in free form or as glycinates (e.g., magnesium glycinate) and it most likely impacts health one way or another - so it should be a research priority.

I'm mostly concerned about glycine supplementation in the context of MSA.

It's really a toss-up.

[Rhyothemis in reply to Rhyothemis]

re: headache - checked amazon reviews for anecdotes and there are reports of glycine both relieving and causing headache symptoms

[Bolt_Upright in reply to Rhyothemis]

I WANT to take Glycine, I really do. Just can't get past this:

rhyobrain.blogspot.com/2020...

High glycine levels are excitotoxic; magnesium can mitigate glycine excitoxicity. Some hypotheses on the therapeutic action of Li relate to its interactions with Mg, either through competitive binding or Li binding in complexes with Mg. Would these types of interactions have an impact on Mg's ability to mitigate glycine excitotoxicity?

Glycine has also been implicated in demyelination.

[Rhyothemis in reply to Bolt_Upright]

It's a conundrum. I really hope we get a good objective, and sensitive (I' may as well dream big if I'm going to dream) that could let individuals know if they are on the right track or not with interventions. I am hoping neurofilament light chain fits the bill. I wrote to Life Extension Foundation customer service about whether they could offer Nfl tests - affordable, direct to consumer testing would be ideal. They said they would consider it.

I think now it would be really beneficial to make Nfl testing widely available as mild/moderate (not hospitalized) Covid patients were found to have elevated Nfl levels post infection - seemed to age them by ~15 years (Nfl goes up with age, but varies a lot by individual). I don't know if there has been follow up to see if it went back down after a few months; hopefully it was just due to olfactory neuron damage. The high interindividual variability of Nfl suggests it is something that could be altered by various types of interventions (diet, exercise, sauna, supplements, Rx drugs).

covid & Nfl - pubmed.ncbi.nlm.nih.gov/326...

Nfl as blood biomarker - pubmed.ncbi.nlm.nih.gov/332...

I think there may be something about glycine and specifically MSA - there has to be a reason MSA is different from PD, maybe it relates to glycine. MSA patients also appear to have lower threshold for Li toxicity (blood levels).

MSA & lithium - pubmed.ncbi.nlm.nih.gov/229...

[Smittybear7]

My homocysteine level is 10.4umol/LIt is flagged as being high on my recent blood test. What's your opinion? Thank you

[Bolt_Upright in reply to Smittybear7]

My opinion? I'm sorry, I don't know much about homocysteine levels. You should make a new post asking this question to the group. Maybe somebody will know. Good luck.

[faridaro in reply to Smittybear7]

The lab I've been using have homocysteine levels <=10.4 listed as normal, but from what I've read on the subject optimal levels are 7-9.