(A non-protection of) Dopamine oxidation metabolites as a cause of Parkinson's disease

[Candeias]

5-S-cysteinyl-dopamine, a neurotoxic endogenous metabolite of dopamine: Implications for Parkinson's disease

"Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and is characterized for being an idiopathic and multifactorial disease. Extensive research has been conducted to explain the origin of the disease, but it still remains elusive. It is well known that dopamine oxidation, through the endogenous formation of toxic metabolites, is a key process in the activation of a cascade of molecular events that leads to cellular death in the hallmark of PD. Thio-catecholamines, such as 5-S-cysteinyl-dopamine, 5-S-glutathionyl-dopamine and derived benzothiazines, are endogenous metabolites formed in the dopamine oxidative degradation pathway. Those metabolites have been shown to be highly toxic to neurons in the substantia nigra pars compacta, activating molecular mechanisms that ultimately lead to neuronal death. In this review we describe the origin, formation and the toxic effects of 5-S-cysteinyl-dopamine and its oxidative derivatives that cause death to dopaminergic neurons. Furthermore, we correlate the formation of those metabolites with the neurodegeneration progress in PD. In addition, we present the reported neuroprotective strategies of products that protect against the cellular damage of those thio-catecholamines. Finally, we discuss the advantages in the use of 5-S-cysteinyl-dopamine as a potential biomarker for PD."

The same study cites things/studies like taurine, vitamin C/E, Q10, GSH, NAC and a wide variety of polyphenolic compounds that decrease cellular damage from these oxidized dopamine compounds and consequently the inhibition of Lewy bodies and neurites accumulation.

Now it seems to me that increasing dopamine in people with imminent Parkinson's (loss of more than 70% of dopaminergic neurons in the substantia nigra pars compacta) will only make the problem even worse. And the ideal scenario would be to increase the consumption of neuroprotective substances that "mitigate mitochondrial dysfunction, reducing both levels of oxidative stress and inflammatory responses, and inhibiting the fibril accumulation of a-syn".
@Mauritio
@haidut
Comments?

 

[mostlylurking]

And the ideal scenario would be to increase the consumption of neuroprotective substances that "mitigate mitochondrial dysfunction, reducing both levels of oxidative stress and inflammatory responses, and inhibiting the fibril accumulation of a-syn".

Thiamine mitigates mitochondrial dysfunction, reduces oxidative stress (reactive oxygen species), and inflammation. Dr. Costantini's work with thiamine for Parkinson's Disease patients may be of interest to you.
You can find Dr. Costantini's papers on his website hiding behind "Blog Posts". Here are a few of them:
High-dose thiamine as initial treatment for Parkinson’s disease

An open-label pilot study with high-dose thiamine in Parkinson’s disease

Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study

additional articles, by other people:

Thiamine Deficiency and Neurodegeneration: The Interplay among Oxidative Stress, Endoplasmic Reticulum Stress and Autophagy

Thiamine (Vitamin B1) is an essential nutrient and indispensable for normal growth and development of the organism due to its multilateral participation in key biochemical and physiological processes. Humans must obtain thiamine from their diet since ...

www.ncbi.nlm.nih.gov

The Beneficial Role of Thiamine in Parkinson Disease

Parkinson disease () is the second most common form of neurodegeneration among elderly individuals. is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. In this paper, we review the evidence for an association ...

www.ncbi.nlm.nih.gov

 

[mostlylurking]

5-S-cysteinyl-dopamine, a neurotoxic endogenous metabolite of dopamine: Implications for Parkinson's disease

"Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and is characterized for being an idiopathic and multifactorial disease. Extensive research has been conducted to explain the origin of the disease, but it still remains elusive. It is well known that dopamine oxidation, through the endogenous formation of toxic metabolites, is a key process in the activation of a cascade of molecular events that leads to cellular death in the hallmark of PD. Thio-catecholamines, such as 5-S-cysteinyl-dopamine, 5-S-glutathionyl-dopamine and derived benzothiazines, are endogenous metabolites formed in the dopamine oxidative degradation pathway. Those metabolites have been shown to be highly toxic to neurons in the substantia nigra pars compacta, activating molecular mechanisms that ultimately lead to neuronal death. In this review we describe the origin, formation and the toxic effects of 5-S-cysteinyl-dopamine and its oxidative derivatives that cause death to dopaminergic neurons. Furthermore, we correlate the formation of those metabolites with the neurodegeneration progress in PD. In addition, we present the reported neuroprotective strategies of products that protect against the cellular damage of those thio-catecholamines. Finally, we discuss the advantages in the use of 5-S-cysteinyl-dopamine as a potential biomarker for PD."

The same study cites things/studies like taurine, vitamin C/E, Q10, GSH, NAC and a wide variety of polyphenolic compounds that decrease cellular damage from these oxidized dopamine compounds and consequently the inhibition of Lewy bodies and neurites accumulation.

Now it seems to me that increasing dopamine in people with imminent Parkinson's (loss of more than 70% of dopaminergic neurons in the substantia nigra pars compacta) will only make the problem even worse. And the ideal scenario would be to increase the consumption of neuroprotective substances that "mitigate mitochondrial dysfunction, reducing both levels of oxidative stress and inflammatory responses, and inhibiting the fibril accumulation of a-syn".
@Mauritio
@haidut
Comments?

I found another article of interest regarding thiamine and dopamine metabolites.

https://www.sciencedirect.com/science/article/abs/pii/S0883944121001039

"Thiamine is a water-soluble vitamin required as a cofactor for pyruvate dehydrogenase (PDH) and Transketolase. [1] PDH facilitates the conversion of pyruvate into acetyl-coenzyme A (CoA). In a thiamine deficient state, pyruvate is shifted towards anaerobic metabolism and converted into lactate. [2] Anaerobic metabolism and lack of adenosine triphosphate in the brain causes accumulation of dopamine metabolites. [2] Transketolase is another thiamine dependent enzyme essential for Gamma Amino Butyric Acid (GABA) synthesis. [2,3] Thus, thiamine deficiency has been associated with delirium from altered dopamine metabolites, GABA level, and lactic acidosis. Thiamine and Vitamin B2 deficiency can negatively impact the bioavailability of the vitamin B3's (niacin) functional cofactor forms found as nicotinamide adenine dinucleotide (NAD+) (phosphate) and reduced forms (referred as NAD(P)(H)) [4], These cofactors are intimately implicated in essential bioenergetics, anabolic and catabolic pathways. Impairment in biosynthesis of NAD+ has been attributed with acute kidney injury (AKI) in critically ill and nicotinamide supplementation is associated with a lower incidence of AKI in a phase I study. [5] The human body cannot synthesize thiamine and storage is limited mostly in skeletal muscles making it prone to deficiency. Thiamine deficiency is reported in as high as 20% of patients in ICU, and 10–70% in patients with sepsis. [1,[6], [7], [8]] This can be attributed to multiple factors including poor absorption, refeeding syndrome due to increased carbohydrate intake resulting in increased requirements for thiamine to metabolize glucose, and medications such as proton pump inhibitors. [1] Furthermore, both enteral and parenteral nutrition have traditionally focused upon calories rather than micronutrients. Thiamine repletion has been previously shown to reduce 28-day mortality in septic shock, number of ventilator-free days, and delirium free days among matched cases. [9] However, prior studies on thiamine repletion in critically ill patients were small and not adequately powered. Thus, in order to fully appraise the available data, we sought to perform this systematic review and meta-analysis."

 

[Mauritio]

It sounds like inhibiting the the breakdown of dopamine into those toxic metabolites makes sense. So if for example MAO-B metabolizes dopamine into those toxic molecules than inhibiting MAO-B makes sense. And MAO-B inhibitors like selegiline are beeing used for parkinsons treatment.

Btw I didnt get a notification that you tagged me, just saw it coincidentally.

 

[Validus]

Looks like an organic compound called alda-1 works too as an agonist of aldehyde dehydrogenase 2.

Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant

In approximately one billion people, a point mutation inactivates a key detoxifying enzyme, aldehyde dehydrogenase (ALDH2). This mitochondrial enzyme metabolizes toxic biogenic and environmental aldehydes, including the endogenously produced 4-hydroxynonenal ...

www.ncbi.nlm.nih.gov

 

[Validus]

So it seems like pesticide exposure reduces aldehyde dehydrogenase, which if I understand correctly, is the enzyme that breaks down and clears the dopamine metabolite DOPALDEHYDE, which it seems may be neurotoxic and not dopamine itself.

It seems like that enzyme is responsible for metabolizing alcohol too...what's interesting is since my really bad case of "covid" 2 years ago, I immediately lost my ability to consume alcohol and not feel incredibly sick the next day.

 

[Validus]

I found a study and in rats the dose of Alda 1 was 50 mg/day.

That converts to about 700 mg per day for a man my weight.

Looking at places like sigma Aldrich, if I could even order it, would cost about $3,000/day, wow.

 

[mostlylurking]

I found a study and in rats the dose of Alda 1 was 50 mg/day.

That converts to about 700 mg per day for a man my weight.

Looking at places like sigma Aldrich, if I could even order it, would cost about $3,000/day, wow.

Thiamine hcl is just a whole lot cheaper, with a much longer history of safety.

 

[Candeias]

I found another article of interest regarding thiamine and dopamine metabolites.

https://www.sciencedirect.com/science/article/abs/pii/S0883944121001039

" Anaerobic metabolism and lack of adenosine triphosphate in the brain causes accumulation of dopamine metabolites. [2] "

Everything linked to defective metabolism (hypothyroidism, PUFAs, serotonin, endotoxin, lack of sunlight/redlight) as Peat always mentioned.

 

[mostlylurking]

Everything linked to defective metabolism (hypothyroidism, PUFAs, serotonin, endotoxin, lack of sunlight/redlight) as Peat always mentioned.

The one that's missing off your list of things that are linked to defective metabolism is thiamine deficiency.

Peat quotes on thiamine:

Ray Peat On Vitamin B1 - Thiamine - LifeGivingStore.com

Ray Peat has written on the importance of Vitamin B1 also known as Thiamine. Here we will gather quotes from Ray Peat about the incredible power of Thiamine

lifegivingstore.com

Thiamine is a very big key to the issue. I'm sorry that Peat didn't emphasize it more than he did. Many things that Ray promoted are detrimental to thiamine function; antibiotic use, coffee, and sugar being some of the major ones.

 

[Candeias]

The one that's missing off your list of things that are linked to defective metabolism is thiamine deficiency.

Peat quotes on thiamine:

Ray Peat On Vitamin B1 - Thiamine - LifeGivingStore.com

Ray Peat has written on the importance of Vitamin B1 also known as Thiamine. Here we will gather quotes from Ray Peat about the incredible power of Thiamine

lifegivingstore.com

Thiamine is a very big key to the issue. I'm sorry that Peat didn't emphasize it more than he did. Many things that Ray promoted are detrimental to thiamine function; antibiotic use, coffee, and sugar being some of the major ones.

By combining these practices and avoiding pork, perhaps a deficiency can be created?
As there are not many good sources.

 

[mostlylurking]

By combining these practices and avoiding pork, perhaps a deficiency can be created?
As there are not many good sources.

Yes. Throw in avoidance of refined flours and junk food and that pretty much assures a thiamine deficiency. There's a reason these things are "fortified" with thiamine. I'm not advocating eating these things though. I'm advocating thiamine supplementation. Thiamine deficiencies are a very big problem.

A Disease Of Modern Civilization Threatens Eradication Of All Life On Planet Earth While World Leaders Are Distracted By The Contrived Crises Of The COVID/Great Reset

 

[Candeias]

Yes. Throw in avoidance of refined flours and junk food and that pretty much assures a thiamine deficiency. There's a reason these things are "fortified" with thiamine. I'm not advocating eating these things though. I'm advocating thiamine supplementation. Thiamine deficiency problems are a very big problem.

A Disease Of Modern Civilization Threatens Eradication Of All Life On Planet Earth While World Leaders Are Distracted By The Contrived Crises Of The COVID/Great Reset

Some questions come to mind when reading all this: what would be the symptoms of a mild deficiency? what other B vitamins could exacerbate it? how much B1 is safe to take alone?

 

[Peater]

Yes. Throw in avoidance of refined flours and junk food and that pretty much assures a thiamine deficiency. There's a reason these things are "fortified" with thiamine. I'm not advocating eating these things though. I'm advocating thiamine supplementation. Thiamine deficiencies are a very big problem.

A Disease Of Modern Civilization Threatens Eradication Of All Life On Planet Earth While World Leaders Are Distracted By The Contrived Crises Of The COVID/Great Reset

Great article. I see it also mentions that heart medication that is franken-iodine.

 

[Candeias]

It sounds like inhibiting the the breakdown of dopamine into those toxic metabolites makes sense. So if for example MAO-B metabolizes dopamine into those toxic molecules than inhibiting MAO-B makes sense. And MAO-B inhibitors like selegiline are beeing used for parkinsons treatment.

Btw I didnt get a notification that you tagged me, just saw it coincidentally.

Hypochlorite converts cysteinyl-dopamine into a cytotoxic product: A possible factor in Parkinson's Disease

"The dopamine oxidation product cysteinyl-dopamine has attracted attention as a contributor to the death of dopaminergic neurons in Parkinson's disease. Treatment of cysteinyl-dopamine with hypochlorite yields an even more cytotoxic product. This product has potent redox-cycling activity and initiates production of superoxide in PC12 cells. Taurine, which scavenges hypochlorite, protects PC12 cells from cysteinyl-dopamine but not from the hypochlorite product, suggesting that the product, not cysteinyl-dopamine itself, is toxic. Furthermore, rotenone, which enhances expression of the hypochlorite-producing enzyme myeloperoxidase, increases the cytotoxicity of cysteinyl-dopamine but not of the hypochlorite product. This suggests that dopamine oxidation to cysteinyl-dopamine followed by hypochlorite-dependent conversion to a cytotoxic redox-cycling product leads to the generation of reactive oxygen species and oxidative stress and may contribute to the death of dopaminergic neurons."

 

[Validus]

Pears, sweet limes, kefir and coconut water...Maybe throw in andrographis and curcumin?

https://www.sciencedirect.com/science/article/pii/S266592711930005X#bib7

 

[J.R.K]

Thiamine mitigates mitochondrial dysfunction, reduces oxidative stress (reactive oxygen species), and inflammation. Dr. Costantini's work with thiamine for Parkinson's Disease patients may be of interest to you.
You can find Dr. Costantini's papers on his website hiding behind "Blog Posts". Here are a few of them:
High-dose thiamine as initial treatment for Parkinson’s disease

An open-label pilot study with high-dose thiamine in Parkinson’s disease

Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study

additional articles, by other people:

Thiamine Deficiency and Neurodegeneration: The Interplay among Oxidative Stress, Endoplasmic Reticulum Stress and Autophagy

Thiamine (Vitamin B1) is an essential nutrient and indispensable for normal growth and development of the organism due to its multilateral participation in key biochemical and physiological processes. Humans must obtain thiamine from their diet since ...

www.ncbi.nlm.nih.gov

The Beneficial Role of Thiamine in Parkinson Disease

Parkinson disease () is the second most common form of neurodegeneration among elderly individuals. is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. In this paper, we review the evidence for an association ...

www.ncbi.nlm.nih.gov

I am re familiarizing myself on the concept of the benefits of carbon dioxides therapeutic properties. Thiamine increases CO2 levels and in a recent interview with Dr Mercola @haidut mentioned that CO2 could breakdown amyloid plaques in Alzheimer’s patients. I am wondering if there is a similar connection with thiamine, CO2, and Parkinson’s here as well?

 

[mostlylurking]

I am re familiarizing myself on the concept of the benefits of carbon dioxides therapeutic properties. Thiamine increases CO2 levels and in a recent interview with Dr Mercola @haidut mentioned that CO2 could breakdown amyloid plaques in Alzheimer’s patients. I am wondering if there is a similar connection with thiamine, CO2, and Parkinson’s here as well?

Increased CO2 is extremely beneficial to living cells as it pulls things like calcium out of the cells when it exits. But thiamine acts in many ways. One way is that it acts as a cofactor for several enzymes in the beginning of the Krebs cycle. Without thiamine, the Krebs cycle gets derailed early on in the process. Without this action, ATP (cellular energy) is not created, and lactic acid is the end product of the cycle instead of carbon dioxide. Nothing can function properly without ATP. The autonomic nervous system is especially dependent on thiamine for additional reasons.

Suggested reading:

How Can Something As Simple as Thiamine Cause So Many Problems? - Hormones Matter

Is thiamine deficiency too simple to explain the devastating nature of the systemic adverse reactions to some vaccines and medications?

www.hormonesmatter.com

View: https://medium.com/eds-perspectives/why-does-high-dose-thiamine-relieve-fatigue-in-individuals-with-diverse-neurological-conditions-40a3502f6439

Italian Neurologist Antonio Costantini MD has discovered his Parkinson's patients show marked improved with receiving High Dose Thiamine.

In this Parkinsons Recovery interview with Robert Rodgers, PhD, founder of Parkinsons Recovery, Dr. Antonio Costantini MD discusses the rationale and benefit of taking high dose thiamine for persons currently experiencing symptoms of Parkinson's disease.

www.blog.parkinsonsrecovery.com

A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives

Thiamin(e), also known as vitamin B1, is now known to play a fundamental role in energy metabolism. Its discovery followed from the original early research on the ‘anti-beriberi factor’ found in rice polishings. After its synthesis in ...

www.ncbi.nlm.nih.gov

I found Dr. Derrick Lonsdale's articles very helpful.

Dr. Costantini's articles on his website have been helpful too.

The youtube videos about thiamine by Elliott Overton are very good.

 

[charlie]

View: https://twitter.com/NutriDetect/status/1738695777554432367?t=N-39_atbssgjOTkLgKSCkA&s=19

 

[J.R.K]

Increased CO2 is extremely beneficial to living cells as it pulls things like calcium out of the cells when it exits. But thiamine acts in many ways. One way is that it acts as a cofactor for several enzymes in the beginning of the Krebs cycle. Without thiamine, the Krebs cycle gets derailed early on in the process. Without this action, ATP (cellular energy) is not created, and lactic acid is the end product of the cycle instead of carbon dioxide. Nothing can function properly without ATP. The autonomic nervous system is especially dependent on thiamine for additional reasons.

Suggested reading:

How Can Something As Simple as Thiamine Cause So Many Problems? - Hormones Matter

Is thiamine deficiency too simple to explain the devastating nature of the systemic adverse reactions to some vaccines and medications?

www.hormonesmatter.com

View: https://medium.com/eds-perspectives/why-does-high-dose-thiamine-relieve-fatigue-in-individuals-with-diverse-neurological-conditions-40a3502f6439

Italian Neurologist Antonio Costantini MD has discovered his Parkinson's patients show marked improved with receiving High Dose Thiamine.

In this Parkinsons Recovery interview with Robert Rodgers, PhD, founder of Parkinsons Recovery, Dr. Antonio Costantini MD discusses the rationale and benefit of taking high dose thiamine for persons currently experiencing symptoms of Parkinson's disease.

www.blog.parkinsonsrecovery.com

A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives

Thiamin(e), also known as vitamin B1, is now known to play a fundamental role in energy metabolism. Its discovery followed from the original early research on the ‘anti-beriberi factor’ found in rice polishings. After its synthesis in ...

www.ncbi.nlm.nih.gov

I found Dr. Derrick Lonsdale's articles very helpful.

Dr. Costantini's articles on his website have been helpful too.

The youtube videos about thiamine by Elliott Overton are very good.

I have listened to many of Elliot Overtons presentations he is very knowledgeable, I find the recurring observations of thiamine and COVID-19 disease symptoms being alleviated by thiamine to be fascinating as well as counterintuitive (but undeniably effective) the idea of oxygen being toxic if introduced to a patient too soon after coming out of shock is new but I understand that the cells are in a hypo metabolic state and just cannot take up the oxygen. I think this knowledge is imperative if we see restrictions on drugs such as acetozolimide as we did in the pandemic. A, large bag a tank of CO2 and a regulator probably would have saved far more lives than ventilators, Medazolam and opioid combinations. Thank you for once again expanding my knowledge on this seemingly overlooked B vitamin @mostlylurking.