Acetylcholine Triggers l-Glutamate Exocytosis via Nicotinic Receptors and Inhibits Melatonin Synthesis in Rat Pinealocytes

[SilentEchoes]

Acetylcholine triggers glutamate excitotoxicity and blocks melatonin synthesis. Nicotine therapy deserves a second look.

SE

Journal of Neuroscience 1 July 1998, 18 (13) 4946-4952; DOI: doi.org/10.1523/JNEUROSCI.1...

[chartist]

It never seems to be simple as suggested by this 2020 study which shows many variables at play and a different outcome depending on the specific circumstances involved in the study. Even age can make a significant difference. Based on the age of the study you linked to, even the testing procedures could have changed over those 22 years.

pubmed.ncbi.nlm.nih.gov/110...

Art

[SilentEchoes in reply to chartist]

I like older studies - research was less likely to suffer from outside influence. Maybe the method is more refined by high tech gadgets but they knew a hell of lot back in 1998.

The pulmonologist only needed a stethoscope to know my breathing problem was my diaphragm and not my lungs. She referred me to a top notch neurologist who she studied under. He only needed a physical exam and basic pulmonary function test to diagnose motor neuron disease, and got me started on a ventilator right away. Early intervention significantly prolongs survival. That's a high tech gadget I can't live without. The iron lung works too 🙂

[Hidden in reply to SilentEchoes]

I know if no evidence that substantiates that older research was less prone to outside influence. Where are you getting that from? the food pyramid came about in the 90’s

[Hidden]

This is not the best example but

pubmed.ncbi.nlm.nih.gov/169...

Point is, it’s quite the opposite

I don’t believe anything until it is shown in multiple studies with some variations in how they are executed.

[SilentEchoes in reply to Hidden]

I'm not sure I understand your comment. Acetylcholine (ACh) is a neurotransmitter that is broken down by Acetylcholinesterase (AChE). It's tightly regulated in our body.

Too much ACh or a lack of AChE is toxic to nerve cells. kaypeeoh tried to euthanize a dog with acetylcholine, it paralyzed the dogs diaphragm. That in a nutshell is ALS. It's is also the toxic mechanism for organophosphate poisoning.

I showed how [excess] Acetylcholine induced glutamate excitotoxicity by blocking the synthesis of melatonin.

Why is this important?

1. Glutamate excitotoxicity causes brain inflammation, the underlying pathology in neurodegenerative diseases.

2. Specifically, it is the pathology that drives motor neuron disease aka ALS.

3. It demonstrates how NDD develops, by overwhelming and disabling our defense system. Is this due to age - rarely IMHO.

Neuromuscular junction dismantling plays a crucial role in the onset of Amyotrophic Lateral Sclerosis (ALS).

The neuromuscular junction is a zone between synapses that enables transfer of information from the nervous system to muscles.

The neuromuscular junction is comprised of a motoneuron that transfers information to a muscle thanks to acetylcholine, a neurotransmitter.

The contact zone between the neuron and muscle is called a synapse, said to be “cholinergic” because it uses acetylcholine as a neurotransmitter.

Once acetylcholine has fulfilled its mission and transferred the necessary information, it is degraded by the enzyme acetylcholinesterase.

Malfunction of the cholinergic system, involving the synapses that use acetylcholine as a neurotransmitter, has been highlighted in many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, and Huntington’s disease along with ALS/FTD.

I hope this helps shed some light on the pathogenesis of NDDs.

❤️🌺❤️🌺

SE

[Hidden]

Edit:

This states it reduces Excitotoxicity

I have yet to read this fully

Quote;

Further experiments showed that acetylcholine also increases the reuptake of glutamate into synaptic vesicles and controls the amount and frequency of glutamate released at habenular synapses.

If it increases the uptake wouldn’t that reduce the Excitotoxicity? No, it increases it? We need reputable inhibitors. Right?

ncbi.nlm.nih.gov/labs/pmc/a...

I wish researching was my full time job bc it’s much more fascinating than what I actually do!

My original response;

It absolutely does help. Thank you!I’m upset bc I have been supplementing with Citicoline as have many others.

I have read / heard from multiple sources, Buck institute doctors and others, that it’s Neuroprotective.

So, my previous response I think was triggered by misunderstanding and denial. I’m getting it now. I and many others have been adding to our degeneration by adding acetylcholine via Citicoline supplementation.

I’m multitasking at the moment so my head is not fully on this and I’m hoping I’m misunderstanding bc it’s pretty darn upsetting that I have been using something detrimental

[Bolt_Upright in reply to Hidden]

I can never figure out if re-uptake inhibitors increase or decrease a molecule

[kaypeeoh in reply to Bolt_Upright]

Just a guess and I'm probably wrong. Uptake is the chemical crossing the BBB. But it can flow back and forth through the BBB. REUPTAKE keeps more drug coming in the brain, Inhibition of reuptake means less drug coming into the brain. None of that means anything when we talk about cell wall attachment.

[Kia17 in reply to kaypeeoh]

Re-uptake has nothing to do with the brain. It can be anywhere. For example; Re-uptake of Thyroid hormone.

To answer Bolt question: re-uptake inhibitors technically letting a hormone/neurotransmitter/ biochemical substances remain in the system more than normally they should . Example: SSRI medications, reduce or inhibit re-absorption (re-uptake) of Seretonin so the duration of staying Seretonin in synaptic space increases. To put it simply, less Seretonin goes wasted.

[Hidden in reply to Kia17]

Well said. Uptake is like transport. Uptake inhibitor inhibits transporting it therefore it stays.

[kaypeeoh]

I've ordered the STOP SMOKING! patches. If I get addicted I'll sue.

In response to silent echoes, in vet med school the teachers taught about drugs attaching to cell wall sites. These sites were like a glove. The drug was like a hand. The hand fits the glove and triggers the cell to react. But if thousands of hands are filling the system they crowd together and nothing gets to the glove. Might sound silly but it's the working theory for the basis of immunology.

[Hidden]

Huperzine A or donepezil instead of nicotine? Same pathway

[SilentEchoes in reply to Hidden]

Please read my reply to kaypeeoh 😊

[Despe in reply to Hidden]

All the links with scientific studies and or trials dot not specifically address PD or ALS in this instance. For a lay person to read let alone understand is rather very difficult. However, from what I concluded, choline, uridine and other nootropics are OUT! Huperzin A or Aricept are IN! That is if I correctly interpreted SE's scientific find.

As I have been saying all along, the BODY needs everything in MODERATION. We could get all the nutrients from the right foods. Variation and moderation in everything we do and eat. My two cents.

[SilentEchoes in reply to Despe]

Thank you. My opinions are specific to me and general for everyone else.

On another post we discussed the value of NMDA blockers. In my case, I have known antiNMDA receptor antibodies and the NMDA antagonist memantine shows promise. PD patients are sometimes prescribed amantadine. This inferrs NMDA pathology in Parkinson's disease.

There are natural NMDA blockers, but I need to rescue myself and quickly. Too high of a dose of magnesium makes my fasciculations worse.

If you have diagnosed or undiagnosed schizophrenia, the NMDA blockers will make your condition worse. You need to know your status and pay attention to your body.

Like most on this forum, tests and relevant information has been withheld. Some don't want to know and I think they are doing themself a disservice and risk harming themselves.

I know that I have ALS and I have other diagnosis that are common in PD. Should you increase acetylcholine or suppress acetylcholinesterase? In my case, the acetylcholine levels are toxic (no huperzine) and I need to increase acetylcholinesterase (high dose melatonin initially).

I agree that we need to practice moderation in all things. I credit outliving my prognosis by eating clean. But it's not enough, I'm still declining.

You cannot hope to heal in the same environment in which you got sick. We are constantly making adjustments - maybe that's just life.

[Hidden in reply to Despe]

Please read this summary. It echoes all that I have been reading about Citicoline but is presented in a more concise way.

Quote;

“The neuroprotective effects of citicoline may also be due to its likely ability to raise levels of serotonin and lower glutamate levels.”

blog.designsforhealth.com/n...

[Despe in reply to Hidden]

Excellent! Even Dr. Mischley had recommended CitiColine. I shouldn't have doubted it.

[kaypeeoh]

What about Huperzine AND Nicotine?

[SilentEchoes in reply to kaypeeoh]

Be careful not to overdo it, otherwise you'll get the opposite neurotoxic effect.

ncbi.nlm.nih.gov/pmc/articl...

"Huperzine A is a potent and reversible inhibitor of acetylcholinesterase."

This makes Huperzine A a no go for me. We need to promote AChE production not inhibit it.

"Huperzine A prevents glutamate-induced calcium mobilization in cell cultures." Through which receptors? Huperzine-A is also a NMDA receptor antagonist. That's good, but is it a selective or indiscriminate inhibitor? You get neurotoxic effects if you overdo it.

"Huperzine A was shown to ameliorate hydrogen peroxide-induced oxidative injury by enhancing the activities of endogenous antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase."

We can get the same effect with melatonin without disruption of acetycholinesterase.

P.S. Art, you should like this one - it's from 2020 researchgate.net/publicatio...

[Despe in reply to SilentEchoes]

Conclusion

The manifold pharmacological effects of (−)-huperzine A (1), especially when considered in the context of its favorable toxicity profile, argue for its development for the treatment of neurological disorders. Although further study is required to fully elucidate the precise mechanisms underlying these effects, available evidence suggests (−)-huperzine A (1) is superior to many existing antineurodegenerative agents and may operate, in some instances, by orthogonal mechanisms. A long-standing impediment to the clinical development of (−)-huperzine A (1), especially in the United States, has been the lack of a stable and economical source of the metabolite. Recent advances in the total synthesis of (−)-huperzine A (1) may provide a solution to this latter problem.

Did I miss anything?

[chartist in reply to SilentEchoes]

SE,

Yes, I like that it further highlights the myriad of health effects that melatonin offers. I mainly only talk about PD related effects of melatonin on this forum, but there is so much more to melatonin than what I post here.

Art

[Hidden]

Citicoline Neuroprotective?

Quote:

Citicoline is neuroprotective in various animal (preclinical) experimental paradigms. The compound has offered marked neuroprotection in several in vitro and in vivo models of acute and chronic brain ischaemic and neurodegenerative diseases, including brain hypoxia, ischaemia and intracerebral haemorrhage (reviewed by Adibhatla and Hatcher [30]), brain and spinal cord trauma [31], in vitro glutamate excitotoxicity [32, 33] and in vivo amyloid toxicity [34]. However, the mechanisms of this neuroprotection are far from being understood.

ncbi.nlm.nih.gov/labs/pmc/a...

Citicoline potentially a Sirt 1 activator (Sirt 1 changes gene expression)

Quote:

treatment with citicoline has been found to increase sirtuin-1 (SIRT1) protein levels in cultured neurons, in circulating blood mononuclear cells and in the brain. This effect seems to be of critical importance for neuroprotection in experimental stroke because sirtinol, a specific inhibitor of SIRT1 which, by itself, does not influence infarct volume, has been shown to abolish the neuroprotection offered by citicoline. Citicoline displayed a potent synergistic effect with resveratrol (which is known to be a SIRT1 activator), leading to a 60 % reduction in the experimental infarct volume in rats when both drugs were used in doses that were individually ineffective. Moreover, citicoline was ineffective in SIRT1 knock-out homozygotic mice subjected to focal brain ischaemia. However, detailed mechanistic explanations for all of these effects are lacking. For example, there is no explanation as to how citicoline administration leads to attenuation of MAPK activity and increases sirtuin-1 protein content in brain tissues; in particular, does the drug act extracellularly, or is resynthesis of CDP-choline inside brain cells a prerequisite?

Huge in human trial, not effective , not understood why. Maybe it is bc it promotes glutamate Excitotoxicity?

Quote:

Whereas several previous small clinical studies had achieved promising results, two recent large randomized multicenter trials—the COBRIT (Citicoline Brain Injury Treatment) trial performed in 1,213 patients with traumatic brain injury [43], and the international, randomized, multicentre, placebo-controlled sequential ICTUS (International Citicoline Trial on Acute Stroke) trial performed in 2,298 patients with moderate-to-severe acute ischaemic stroke [44]—led to the conclusion that citicoline is not efficacious in these clinical settings. The negative outcomes of these studies were deemed surprising and prompted a few comments, which focused mostly, although not exclusively, on methodological aspects of the evaluation of the clinical effects of the drug [45–47]. What was not commented on was the lack of a mechanistic explanation for the putative neuroprotective properties of citicoline.

Quote

liposomal formulations of citicoline are significantly more neuroprotective

Quote / Conclusion

there is continuing interest in the neuroprotective properties of citicoline. The drug is non-toxic, and numerous preclinical data support the view that it displays neuroprotective properties. However, no adequate mechanistic explanation for these observations has ever been provided.

Glutamate Excitotoxicity was stated but not elaborated upon and in the context it was stated I believe it was meant that it protects against glutamate Excitotoxicity.

ncbi.nlm.nih.gov/labs/pmc/a...

References for this paper include two that refer to it as being protective against glutamate Excitotoxicity.

Quote

32. Matyja E, Taraszewska A, Naganska E, Grieb P,

Rafatowska J. CDP-choline protects motor neurons

against apoptotic changes in a model of chronic

glutamate excitotoxicity in vitro. Folia Neuropathol.

2008;46:139-148. [PubMed] [Google Scholar]

33. Mir C, Clotet J, Aledo R, Durany N, Argemi J,

Lozano R, Cervós-Navarro J, Casals N. CDP-

choline prevents glutamate-mediated cell death in

cerebellar granule neurons. J Mol Neurosci.

2003;20:53-60. doi:10.1385/JMN:20:1:53.

Links to the aforementioned studies

pubmed.ncbi.nlm.nih.gov/185...

pubmed.ncbi.nlm.nih.gov/126...

Is Citicoline vindicated and it is protective as I had thought? The same would then likely apply to uridine.

[Hidden]

Quote@Citicoline lowers increased glutamate concentrations and raises decreased ATP concentrations induced by ischemia. Citicoline also increases glutamate uptake by increasing expression of EAAT2, a glutamate transporter, in vitro in rat astrocytes.”

Uptake means transport. I believe then that would mean reducing its toxicity whereas an uptake inhibitor would keep the glutamate from being transported.

[SilentEchoes in reply to Hidden]

CC, I would err on the side of caution. We want the most elegant solution. This means taking the least amounts of supplements necessary to achieve efficacy. More is not better as Bolt_Upright recently pointed out.

"Treatment with citicoline has been found to increase sirtuin-1 (SIRT1) protein levels in cultured neurons, in circulating blood mononuclear cells and in the brain. 'There is no explanation as to how citicoline administration leads to attenuation of MAPK activity and increases sirtuin-1 protein content in brain tissues.'"

"Huge in human trial, not effective, not understood why." This is a red flag warning.

You aren't going to want to hear this: "Our findings provide new evidence for a direct effect of melatonin on hypoxic microglia through SIRT1, which appears as a potential pharmacological target against hypoxic-derived neuronal damage."

pubmed.ncbi.nlm.nih.gov/321...

An elegant solution is used in mathematics, engineering and software development to refer to a solution that solves the problem in the simplest and most effective manner.

Another engineering principle: No defect forward. Problems magnify up the chain.

Melatonin checks a lot of boxes for me and has a wide margin of safety. I don't want to injure myself in a way that can't be undone. Therefore, citicholine is a no go for me. ❤️🌺❤️🌺

[Hidden in reply to SilentEchoes]

Erring on the side of caution is relative. I take melatonin. I’m very concerned about long term use of extremely high doses of it.

The effect indefinite use of high dose melatonin has on glutamate Excitotoxicity is unknown or the long term effect on the brain in general is unknown.

I have not seen a long term study of high dose melatonin.

Which is why I have been very concerned about HIGH DOSE melatonin being repeatedly encouraged on this forum.

As you may or may not have seen, I have asked questions repeatedly about high dose melatonin to which there has been a response but no answer.

Regarding your husbands credentials, that is excellent but has no relevance. The sources, trials, science is what is relevant.

Summary, high dose melatonin (in excess of 15mg) used indefinitely to stave of neurodegeneration is ill-advised.

[SilentEchoes]

Noted and edited.

I've been thinking about this a lot today, the first step should be a high dose rescue protocol that tapers as symptoms improve. Other supplements can be added at this time.

You wouldn't want to take high dose steroids for very long, but if you need them to save your life, then you're glad it's available.

I'm expressing my opinion, for what it's worth. 🕊️

SE

[Hidden in reply to SilentEchoes]

I agree completely and am relieved you do. If I come off as feisty, I really don’t mean to be. I truly care and therefore get concerned.

[Despe]

What about Lions Mane, Gingko Biloba and Bacopa Monieri? Stop those, too? If you know on top of your head their relationship to glutamate. I will do some searching about that later.

Thank you, SE!

[SilentEchoes in reply to Despe]

It's been a while since I evaluated them. As I recall they're beneficial. Resveratrol is high on my list.

[Hidden in reply to SilentEchoes]

Trans Resveratrol and Pterostilbene are both good Sirt 1 activators.

[Hidden in reply to Despe]

Regarding Citicoline, out of an abundance of caution I’m pausing and researching. I would not rule it out completely, just pause for now. Note, it is recommended by Dr. Dale Bredesen who founded the Buck Institute and has researched ALZ for 30 years. I wrote to him a long time ago and he responded that his protocol is also good for PD.

He also recommends bacopa and Ginko.

Quote:

Citicoline lowers increased glutamate concentrations and raises decreased ATP concentrations induced by ischemia. Citicoline also increases glutamate uptake by increasing expression of EAAT2, a glutamate transporter, in vitro in rat astrocytes. It is suggested that the neuroprotective effects of citicoline after a stroke are due in part to citicoline's ability to decrease levels of glutamate in the brain.[25]

End quote

Uptake means transport.

“Citicoline’s ability to decrease levels of glutamate in the brain.”

en.m.wikipedia.org/wiki/Cit...

(Not that Wikipedia is always a good source but it’s what I started with and it’s concise)

Regarding Ginko,

pubmed.ncbi.nlm.nih.gov/264...

I know you were asking SE but I too have researched this

[Despe in reply to Hidden]

CC,

Thank you! I added Ginkgo and Bacopa about 4 years ago, after reading Bredesen's protocol plus some other Nootropics sites.

I will have him (hubby) contrinue Phosphatidylcholine and Uridine, plus

Ω3, but that will be after food as Ω3 are fat soluble. I will also add Huperzine A a couple of times a week. On those days, no Uridine and Choline. IWO, I will alternate these two powerful supplements.

[SilentEchoes]

I bought a big bag of Chaga mushroom and have a combo with Lions Mane. I'm doing a stool culture to find out what's going on in my gut. Need to see if I should hold off on mushrooms until I get my leaky gut under control. Some/all of my problem could be related to acetylcholine excess 🤷🏼‍♀️

[rebtar]

Terry Wahls also recommends phosphatidylcholine, which is a precursor of choline for acetylcholine synthesis. Liposomal.

terrywahls.com/phosphatidyl...

[Hidden]

SE, Citicoline looks to be beneficial and the post is therefore misleading. Here is another quote and link.

Quote

Cognitive function in older adults

Cognitive function, including the domains of memory, speed, and executive function, decline gradually with increasing age. The rate of cognitive decline is also influenced by modifiable risk factors like dietary habits. Deficiency in B-vitamins and elevated homocysteine concentrations in the blood have been associated with cognitive impairments in the elderly. Yet, a recent meta-analysis of 11 trials indicated that homocysteine lowering using B-vitamin supplementation fails to limit cognitive decline or improve cognitive performance in older adults (58). The cross-sectional data analysis of a subgroup of 1,391 volunteers (ages, 36-83 years) from the large Framingham Heart Study Offspring cohort has indicated that dietary choline intake was positively associated with specific cognitive functions, namely verbal memory and visual memory (59). Another cross-sectional study of 2,195 individuals (ages, 70-74 years) from the Hordaland Health Study examined cognitive abilities and blood concentrations of various determinants of circulating homocysteine, including choline

lpi.oregonstate.edu/mic/oth...