Caffeine And Progression Of Parkinson Disease: A Deleterious Interaction With Creatine

Zpol

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More on the GRIN2A genotype that was briefly mentioned in the study...
Caffeine, creatine, GRIN2A and Parkinson's disease progression
Abstract
Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p = 0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.​

I would like to learn more about this GRIN2A thing but I don't want to purchase the full text of this study, so if anyone has some links or info they could share, that'd be awesome.

I don't have PD but I would think that anything that would increase the rate of progression of this terrible disease would not be good for disease prevention either.
Before reading about the GRIN2A issue, it sounded like the problem was more from the Levdopa interaction or possibly the participants in the high caffeine+creatine group were drinking dangerous sports drinks and doing high-stress inducing workouts and that's what caused increased progression. Now I'm not so sure. Or maybe those factors are what caused the gene variant.
Would those of us taking dopaminergic supplements along with creatine and coffee be at the same risk (of having spare methyl groups)?
So much to consider.
 

Ron J

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More on the GRIN2A genotype that was briefly mentioned in the study...
Caffeine, creatine, GRIN2A and Parkinson's disease progression
Abstract
Caffeine is neuroprotective in animal models of Parkinson's disease (PD) and caffeine intake is inversely associated with the risk of PD. This association may be influenced by the genotype of GRIN2A, which encodes an NMDA-glutamate-receptor subunit. In two placebo-controlled studies, we detected no association of caffeine intake with the rate of clinical progression of PD, except among subjects taking creatine, for whom higher caffeine intake was associated with more rapid progression. We now have analyzed data from 420 subjects for whom DNA samples and caffeine intake data were available from a placebo-controlled study of creatine in PD. The GRIN2A genotype was not associated with the rate of clinical progression of PD in the placebo group. However, there was a 4-way interaction between GRIN2A genotype, caffeine, creatine and the time since baseline. Among subjects in the creatine group with high levels of caffeine intake, but not among those with low caffeine intake, the GRIN2A T allele was associated with more rapid progression (p = 0.03). These data indicate that the deleterious interaction between caffeine and creatine with respect to rate of progression of PD is influenced by GRIN2A genotype. This example of a genetic factor interacting with environmental factors illustrates the complexity of gene-environment interactions in the progression of PD.​

I would like to learn more about this GRIN2A thing but I don't want to purchase the full text of this study, so if anyone has some links or info they could share, that'd be awesome.

I don't have PD but I would think that anything that would increase the rate of progression of this terrible disease would not be good for disease prevention either.
Before reading about the GRIN2A issue, it sounded like the problem was more from the Levdopa interaction or possibly the participants in the high caffeine+creatine group were drinking dangerous sports drinks and doing high-stress inducing workouts and that's what caused increased progression. Now I'm not so sure. Or maybe those factors are what caused the gene variant.
Would those of us taking dopaminergic supplements along with creatine and coffee be at the same risk (of having spare methyl groups)?
So much to consider.
Good find. I'm interested in what that "low caffeine intake" dose is.
 

Zpol

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Good find. I'm interested in what that "low caffeine intake" dose is.

I wondered the same (wish they linked to the 2 studies that were referenced). I found this in the "Caffeine And Progression Of Parkinson Disease: A Deleterious Interaction With Creatine" study...
"The low caffeine group was defined as subjects with daily caffeine intake less than or equal to 300 mg. The high caffeine group had caffeine intakes greater than 300 mg per day. This cutoff of 300mg has been used in previous studies Ascherio, 2001 #645;Fernandez-Duenas, 2014 #3085;Ross, 2000 #644;Schwarzschild, 2003 #3082} of health-related impacts of caffeine consumption."
and this...
"we conducted an additional post-hoc analysis of caffeine and rate of progression comparing subjects with very low caffeine intake (<25mg/day; n=662) to those in the high caffeine group (>300mg/day; n=261)"

I'm guessing these ranges are the standards for caffeine consumption analyzations. In the GRIN2A study, they only specified 'high' and 'low' and not 'very low', so I think anything above 300 mg was considered high and 300mg or less is low.

This, also, from the original posted study is worth highlighting...

"An interesting possibility raised by these results is that the association of high caffeine intake with a faster rate of progression among subjects taking creatine may have masked a protective effect of creatine among subjects with low levels of caffeine intake. However, subgroup analyses restricted to subjects in the low caffeine group (<300mg/day; n=1,288) or the very low caffeine group (<25mg/day; n=662) revealed no significant associations of treatment (creatine versus placebo) and rate of progression of PD."

The dose is apparently quite relevant. It's possible these people were just plain overdosing both caffeine and creatine and that's what caused their accelorated decline. Overdosing on anything is not good for anybody, but those of us who are impaired due to gene variants have to be especially careful.
 

Travis

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As long as you're not taking five grams of levodopa per day you, don't really have to worry about excessive methylation of dopamine.
 

Ron J

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That's good to know Travis, now I can continue taking creatine. Zpol, that's precisely the caffeine dose that I've been taking to optimize androgens and not get the progesterone effects of caffeine.
 

Zpol

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As long as you're not taking five grams of levodopa per day you, don't really have to worry about excessive methylation of dopamine.

That's good to know Travis, now I can continue taking creatine. Zpol, that's precisely the caffeine dose that I've been taking to optimize androgens and not get the progesterone effects of caffeine.

Yes, I am confident now that my 3-5 grams per day of creatine plus 2 to 3 cups coffee is just fine. I'm taking some dopaminergic supp's too but in moderation, and certainly no levodopa.
 

Travis

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I've done some reading on Parkinson's, and the old studies in Guam showed a high prevalence. Guam is unique because they had high aluminum water with a low calcium diet—giving a large percentage of the population Alzheimer's, Parkinson's, and ALS. This aluminum has been determined in the spinal cords of Guam residents, and aluminum expert Daniel Perl saw little difference between Parkinson's and Alzheimer's; the difference comes down to what part of nervous system aluminum distributes. All of the experimental Parkinson's done on mice is reversible, since they use a small molecule drug called MPTP; the substantia nigra can regenerate in the absense of proteolysis‐resistant aluminum inclusion bodies. Parkinson's is characterized by an inclusion body, the Lewy body, which is a conglomerate of lipid peroxidation chains crosslinking proteins containing a sporadic distribution of iron and aluminum ions. The association between Parkinson's and cocaine probably lies in the fact that cocaine has aluminum at a concentrations of ~4·mg/kg, introduced through crushed limestone from the acid/base extraction procedure.

Many researchers think that main Parkinson's symptoms—besides permanent brain changes—come exclusively from methyldopamine (a.k.a. methoxytyramine). Levodopa has been give to Parkinson's patients in gram amounts for decades, and the characteristic Parkinson's bradykinesia could perhaps be explained by this alone. Because otherwise, with the proper dopamine levels, Parkinson's is basically Alzheimer's with a slightly different brain aluminum distribution.

Amyotrophic lateral sclerosis appears to be a little more aluminum in the spinal cord, and a little less in the brain.


Perl, Daniel P. "Alzheimer's disease and Parkinson's disease: distinct entities or extremes of a spectrum of neurodegeneration?." Annals of neurology (1998).
Good, Paul F. "Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study." Brain research (1992)
Piccardo, P. "Histochemical and X-ray microanalytical localization of aluminum in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam." Acta neuropathologica (1988)
Kasarskis, Edward J. "Aluminum, calcium, and iron in the spinal cord of patients with sporadic amyotrophic lateral sclerosis using laser microprobe mass spectroscopy: a preliminary study." Journal of the neurological sciences (1995)
 

Mossy

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...perhaps some interaction between levodopa and creatine.'
...Levodopa has been give to Parkinson's patients in gram amounts for decades, and the characteristic Parkinson's bradykinesia could perhaps be explained by this alone. Because otherwise, with the proper dopamine levels, Parkinson's is basically Alzheimer's with a slightly different brain aluminum distribution.
Hey Travis, I'm attempting discern the good and bad of levodopa from your comments, but my gray matter is lacking. My symptoms throughout the last 7 years tend to show me being susceptible to Parkinson's or Alzheimer's, depending on how things sway. I've used creatine in the past with successful results, and am now drinking coffee. Coincidentally, I'm wanting to add mucuna pruriens (levodopa) as a supplement, which in the past seems to have had a positive effect on me. Should I avoid this, in combination with creation and/or coffee? Thanks for any help.
 

Zpol

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Hey Travis, I'm attempting discern the good and bad of levodopa from your comments, but my gray matter is lacking. My symptoms throughout the last 7 years tend to show me being susceptible to Parkinson's or Alzheimer's, depending on how things sway. I've used creatine in the past with successful results, and am now drinking coffee. Coincidentally, I'm wanting to add mucuna pruriens (levodopa) as a supplement, which in the past seems to have had a positive effect on me. Should I avoid this, in combination with creation and/or coffee? Thanks for any help.

I am very interested to hear what @Travis has to say about this. From what he has explained, levodopa would accelerate PD when/if taken in a caffeine+creatine regimen (independant of whether the levodopa was from all natural mucuna pruriens or pharmaceutical), and therefore would be dangerous. There is some evidence that it would only be deleterious if you have the specific GRIN2A genotype variant. Also as indicated by @Travis, it is the levodopa itself possibly causing the dyskinesia, even when taken on it's own and so probably best avoid levodopa entirely.

Levodopa is considered to be a dopamine 'replacement' and the patient would have to take more and more as the disease progresses and ultimately have to stop due to disabling side effects. And what's more, it can disrupt the body's own dopamine synthesis (arguably may cause resistance). It may have desirable effects but it's not correcting any underlying issue (it'd be like a band-aid), and it's effects may covering up that underlying issue so you won't have the symptoms to use as a marker of healing.

What do you all think about a dopaminergic as opposed to levodopa; do you think it would still cause the accelorated symptoms when taken in a caffeine+creatine regimen?

Factor SA1.
Author information

Abstract
The question of whether to use levodopa (LD) or dopamine agonists as initial therapy in Parkinson's disease has been a controversy for nearly 20 years. There are several issues relating to this treatment regimen that may effect ones decision. Review of them results in the following conclusions: LD does not cause the onset of motor fluctuations and dyskinesia; it probably relates to disease progression. Tolerance does not develop with long-term LD therapy. LD is not toxic. LD decreases mortality in Parkinson's disease. Motor fluctuations can occur with dopamine-agonist monotherapy, but the actual frequency is as yet unknown. Dopamine agonists are not neuroprotective. Clinical trials have indicated that LD remains the most potent symptomatic therapeutic agent available. Dopamine agonists do provide some symptomatic relief when used alone in early Parkinson's disease. Standard preparations of LD have the same effect on early disease as controlled release preparations. Dopamine agonists cause less dyskinesia and fluctuations. These conclusions indicate that both drugs are effective symptomatic agents with their own positive and negative aspects. There is no incorrect choice. It is reasonable to start young onset patients (younger than 50 years of age) with an agonist, because they seem to be more prone to develop motor fluctuations and dyskinesia. However, if employment is in jeopardy then LD may be needed. Because agonists cause more hallucinations, freezing, and somnolence, problems of particular relevance to the elderly (older than 70 years), then LD would be the best agent for older onset patients. In general, but particularly for those falling in between these age groups, treatment should be individualized. In this time of cost effectiveness, LD remains the least expensive of these agents.​

It's confusing to me this article states Levodopa does not cause motor fluctuations dyskinesia, but that when compared to dopamine agonists, the latter causes less fluctuations and dyskinesia!?! this is contradictory.
Here's another comparison...

Parkinson's Disease: Levodopa Versus Dopamine Agonists - Topic Overview
In an effort to delay the development of motor fluctuations, many doctors are now starting people with early Parkinson's disease on a dopamine agonist rather than levodopa. A dopamine agonist may be used until it no longer adequately relieves symptoms, at which point the person starts taking levodopa in addition to the dopamine agonist. (Dopamine agonists can also cause severe sleep problems, hallucinations, and impulse control issues in some people. Having these side effects may be another reason to switch to levodopa.) As long as the person's symptoms are adequately controlled and he or she can tolerate the drug, dopamine agonists may be a good choice for treating early Parkinson's disease.

This approach is being used particularly in younger people with Parkinson's disease, because it can delay the need for levodopa and thus may postpone the motor fluctuations that occur with long-term levodopa therapy. The American Academy of Neurology now recommends this course of treatment for most people with early Parkinson's disease, regardless of their age.​

Sounds like a dopamine agonist would be better than levodopa for those of us with a risk of PD, but still not sure how this would affect those of us on a caffeine+creatine regimen.

I've done some reading on Parkinson's, and the old studies in Guam showed a high prevalence. Guam is unique because they had high aluminum water with a low calcium diet—giving a large percentage of the population Alzheimer's, Parkinson's, and ALS. This aluminum has been determined in the spinal cords of Guam residents, and aluminum expert Daniel Perl saw little difference between Parkinson's and Alzheimer's; the difference comes down to what part of nervous system aluminum distributes. All of the experimental Parkinson's done on mice is reversible, since they use a small molecule drug called MPTP; the substantia nigra can regenerate in the absense of proteolysis‐resistant aluminum inclusion bodies. Parkinson's is characterized by an inclusion body, the Lewy body, which is a conglomerate of lipid peroxidation chains crosslinking proteins containing a sporadic distribution of iron and aluminum ions. The association between Parkinson's and cocaine probably lies in the fact that cocaine has aluminum at a concentrations of ~4·mg/kg, introduced through crushed limestone from the acid/base extraction procedure.

Many researchers think that main Parkinson's symptoms—besides permanent brain changes—come exclusively from methyldopamine (a.k.a. methoxytyramine). Levodopa has been give to Parkinson's patients in gram amounts for decades, and the characteristic Parkinson's bradykinesia could perhaps be explained by this alone. Because otherwise, with the proper dopamine levels, Parkinson's is basically Alzheimer's with a slightly different brain aluminum distribution.

Amyotrophic lateral sclerosis appears to be a little more aluminum in the spinal cord, and a little less in the brain.


Perl, Daniel P. "Alzheimer's disease and Parkinson's disease: distinct entities or extremes of a spectrum of neurodegeneration?." Annals of neurology (1998).
Good, Paul F. "Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study." Brain research (1992)
Piccardo, P. "Histochemical and X-ray microanalytical localization of aluminum in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam." Acta neuropathologica (1988)
Kasarskis, Edward J. "Aluminum, calcium, and iron in the spinal cord of patients with sporadic amyotrophic lateral sclerosis using laser microprobe mass spectroscopy: a preliminary study." Journal of the neurological sciences (1995)

Thank you for this info. I have already quit using aluminium cookware, stopped eating and drinking anything from a can, and switched to spring water. I hope this will have a big impact on prevention.
 

Travis

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Hey Travis, I'm attempting discern the good and bad of levodopa from your comments, but my gray matter is lacking. My symptoms throughout the last 7 years tend to show me being susceptible to Parkinson's or Alzheimer's, depending on how things sway. I've used creatine in the past with successful results, and am now drinking coffee. Coincidentally, I'm wanting to add mucuna pruriens (levodopa) as a supplement, which in the past seems to have had a positive effect on me. Should I avoid this, in combination with creation and/or coffee? Thanks for any help.
I think you have to assume to individuals diagnosed with Parkinson's in the study under review were taking the obligatory levodopa. Since levodopa interacts with methylgroups to form the notorious O‐methyldopa (3‐methoxytyramine), taking methylgroups with levodopa would be expected to increase the concentration of this metabolite. There are researchers who seem to think that O‐methyldopa is equivalent to many Parkinson's symptoms, and the formation of this is under the influence of the 'methyl pool' and the activity of catechol‐O‐methyltransferase. This enzyme can be safely inhibited with epicatechin gallate, found in high concentrations in green tea. However, green tea also has fluoride; this fact would make me add fluoride's natural antidote—boron—to the tea.

I think it's imperative that everyone avoid aluminum, despite the assurances from ALCOA and the FDA that it's safe.

Levodopa seems safe; caffeine appears safe; creatine appears safe; but the interaction of high levels of S‐adenosylmethionine with levodopa—especially with the high catechol‐O‐methyltransferase activity from the val¹⁵⁸ allele—could be expected to lead to the dangerous O‐methyldopa. This can be diminished with green tea, or the restriction of methylators while on levodopa. As long as the symptoms of O‐methyldopa are known, and how it's formed, than there should be no real danger. This is a normal metabolite but high concentrations should be avoided.

Creatine spares methyl groups, and would be expected to raise the water line of the hypothetical 'methyl pool.' People taking levodopa would be expected to have more methylated levodopa (precursor to O‐methyldopamine, or 3‐methoxytyramine) while also taking things like methionine, betaine, and creatine.
 
Last edited:

Mito

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I think it's imperative that everyone avoid aluminum, despite the assurances from ALCOA and the FDA that it's safe.
Mainly dietary aluminum? Or are topical aluminum chlorohydrate and aluminum-zirconium tetrachlorohydrate in antiperspirants problematic too?
 

Travis

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Mainly dietary aluminum? Or are topical aluminum chlorohydrate and aluminum-zirconium tetrachlorohydrate in antiperspirants problematic too?
I think there's actually been a few studies on that. This could be something interesting to look into. Of the top of my head, I'm fairly certain that it has been proven to actually be absorbed.
 

Mossy

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I think you have to assume to individuals diagnosed with Parkinson's in the study under review were taking the obligatory levodopa. Since levodopa interacts with methylgroups to form the notorious O‐methyldopa (3‐methoxytyramine), taking methylgroups with levodopa would be expected to increase the concentration of this metabolite. There are researchers who seem to think that O‐methyldopa is equivalent to many Parkinson's symptoms, and the formation of this is under the influence of the 'methyl pool' and the activity of catechol‐O‐methyltransferase. This enzyme can be safely inhibited with epicatechin gallate, found in high concentrations in green tea. However, green tea also has fluoride; this fact would make me add fluoride's natural antidote—boron—to the tea.

I think it's imperative that everyone avoid aluminum, despite the assurances from ALCOA and the FDA that it's safe.

Levodopa seems safe; caffeine appears safe; creatine appears safe; but the interaction of high levels of S‐adenosylmethionine with levodopa—especially with the high catechol‐O‐methyltransferase activity from the val¹⁵⁸ allele—could be expected to lead to the dangerous O‐methyldopa. This can be diminished with green tea, or the restriction of methylators while on levodopa. As long as the symptoms of O‐methyldopa are known, and how it's formed, than there should be no real danger. This is a normal metabolite but high concentrations should be avoided.

Creatine spares methyl groups, and would be expected to raise the water line of the hypothetical 'methyl pool.' People taking levodopa would be expected to have more methylated levodopa (precursor to O‐methyldopamine, or 3‐methoxytyramine) while also taking things like methionine, betaine, and creatine.
I appreciate the thorough answer. I'm going to have to mull over and let it all sink in, but ultimately the "notorious O-methyldopa" is enough to scare me away from taking levodopa -- though, as you mention, I could add green tea. Even so, I think I'll keep it as simple as I can, and avoid that complex balancing act. At the least, I think I'll wait until I have an idea what O-methyldopa symptoms would consist of, so I know what I'm looking for and can measure it.

Interesting about aluminum. Like many people, I drink soda from a can; so, looks like I'll have to find an alternative.


Thanks again.
 

Mossy

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I am very interested to hear what @Travis has to say about this. From what he has explained, levodopa would accelerate PD when/if taken in a caffeine+creatine regimen (independant of whether the levodopa was from all natural mucuna pruriens or pharmaceutical), and therefore would be dangerous. There is some evidence that it would only be deleterious if you have the specific GRIN2A genotype variant. Also as indicated by @Travis, it is the levodopa itself possibly causing the dyskinesia, even when taken on it's own and so probably best avoid levodopa entirely.

Levodopa is considered to be a dopamine 'replacement' and the patient would have to take more and more as the disease progresses and ultimately have to stop due to disabling side effects. And what's more, it can disrupt the body's own dopamine synthesis (arguably may cause resistance). It may have desirable effects but it's not correcting any underlying issue (it'd be like a band-aid), and it's effects may covering up that underlying issue so you won't have the symptoms to use as a marker of healing.

What do you all think about a dopaminergic as opposed to levodopa; do you think it would still cause the accelorated symptoms when taken in a caffeine+creatine regimen?

Factor SA1.
Author information

Abstract
The question of whether to use levodopa (LD) or dopamine agonists as initial therapy in Parkinson's disease has been a controversy for nearly 20 years. There are several issues relating to this treatment regimen that may effect ones decision. Review of them results in the following conclusions: LD does not cause the onset of motor fluctuations and dyskinesia; it probably relates to disease progression. Tolerance does not develop with long-term LD therapy. LD is not toxic. LD decreases mortality in Parkinson's disease. Motor fluctuations can occur with dopamine-agonist monotherapy, but the actual frequency is as yet unknown. Dopamine agonists are not neuroprotective. Clinical trials have indicated that LD remains the most potent symptomatic therapeutic agent available. Dopamine agonists do provide some symptomatic relief when used alone in early Parkinson's disease. Standard preparations of LD have the same effect on early disease as controlled release preparations. Dopamine agonists cause less dyskinesia and fluctuations. These conclusions indicate that both drugs are effective symptomatic agents with their own positive and negative aspects. There is no incorrect choice. It is reasonable to start young onset patients (younger than 50 years of age) with an agonist, because they seem to be more prone to develop motor fluctuations and dyskinesia. However, if employment is in jeopardy then LD may be needed. Because agonists cause more hallucinations, freezing, and somnolence, problems of particular relevance to the elderly (older than 70 years), then LD would be the best agent for older onset patients. In general, but particularly for those falling in between these age groups, treatment should be individualized. In this time of cost effectiveness, LD remains the least expensive of these agents.​

It's confusing to me this article states Levodopa does not cause motor fluctuations dyskinesia, but that when compared to dopamine agonists, the latter causes less fluctuations and dyskinesia!?! this is contradictory.
Here's another comparison...

Parkinson's Disease: Levodopa Versus Dopamine Agonists - Topic Overview
In an effort to delay the development of motor fluctuations, many doctors are now starting people with early Parkinson's disease on a dopamine agonist rather than levodopa. A dopamine agonist may be used until it no longer adequately relieves symptoms, at which point the person starts taking levodopa in addition to the dopamine agonist. (Dopamine agonists can also cause severe sleep problems, hallucinations, and impulse control issues in some people. Having these side effects may be another reason to switch to levodopa.) As long as the person's symptoms are adequately controlled and he or she can tolerate the drug, dopamine agonists may be a good choice for treating early Parkinson's disease.

This approach is being used particularly in younger people with Parkinson's disease, because it can delay the need for levodopa and thus may postpone the motor fluctuations that occur with long-term levodopa therapy. The American Academy of Neurology now recommends this course of treatment for most people with early Parkinson's disease, regardless of their age.​

Sounds like a dopamine agonist would be better than levodopa for those of us with a risk of PD, but still not sure how this would affect those of us on a caffeine+creatine regimen.



Thank you for this info. I have already quit using aluminium cookware, stopped eating and drinking anything from a can, and switched to spring water. I hope this will have a big impact on prevention.
Thanks Zpol. I appreciate all the brains on this forum who offer up their knowledge. The dependency aspect of levodopa is new to me, so thanks for that.
 

Travis

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I appreciate the thorough answer. I'm going to have to mull over and let it all sink in, but ultimately the "notorious O-methyldopa" is enough to scare me away from taking levodopa -- though, as you mention, I could add green tea. Even so, I think I'll keep it as simple as I can, and avoid that complex balancing act. At the least, I think I'll wait until I have an idea what O-methyldopa symptoms would consist of, so I know what I'm looking for and can measure it.

Interesting about aluminum. Like many people, I drink soda from a can; so, looks like I'll have to find an alternative.


Thanks again.
But just remember that we all have O‐methyldopamine in our bodies, and you can take any amount of levodopa. You could always cut‐back if you notice it building‐up.

Here are some experimental observations:

'Moreover, we recently showed that the dopamine metabolite 3-methoxytyramine [3O‐methyldopamine] also causes increased behavioural activity in rats, and that this effect is blocked by a dopamine D₁/D₅ receptor antagonist, suggesting that it is mediated via dopamine D₁/D₅ receptors' ―Nakazato

'Dopamine is metabolised to 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine. Both of these metabolites can be further metabolised to homovanillic acid (HVA). In a previous study, we demonstrated that neither DOPAC nor HVA causes significant behavioural activity and that dopamine-denervated rats exhibit a supersensitive response to 3-methoxytyramine.' ―Nakazato

'Behavioural activity increased significantly only after the injection of 3-methoxytyramine into the medial prefrontal cortex. Moreover, after medial prefrontal cortex injections, the rats exhibited increased locomotion, rotation behaviour (without directional preference), stereotypy (primarily prolonged sniffing), and catalepsy-like posture (getting up and staying in the same position without movement) like that previously observed with intracerebroventricular injections of 3-methoxytyramine (Nakazato and Akiyama, 2002).' ―Nakazato

'The results of the present study show that intracerebroventricular injection of 3-methoxytyramine caused an increase in behavioural activity and stereotypy, indicating that this dopamine metabolite may have a role in the dyskinesia associated with chronic L-DOPA treatment in Parkinson patients.' ―Nakazato

We all eat at least 30 grams of protein per day. A significant amount of this—approximately 5.79% in casein, as a typical example—is tyrosine. This equates to 1.74 grams of tyrosine (30·g·protein·d⁻¹) for a smaller person, and 2.32·g·tyrosine (40·g·protein·d⁻¹) for a slightly larger person. Taking an extra 500 milligrams seems like it would be safe; Parkinson's patients ingest grams of it, even more significant on the low‐protein diet of older people:

'This concept was based on the observation that a slow and gradual reduction in daily dose over 10 months (from an average of 4.2 g/day to 2.7 g/day) abolished oscillations in performance in 18 of 34 patients without significant deterioration in mobility. The conclusion was that many patients were overdosed with levodopa. In the United Kingdom, in contrast to North America, we have by and large used smaller daily doses of levodopa (in our own clinic the average daily dose is about 2–5 g).' ―Marsden

With milligram amounts, and perhaps bromocriptine, I don't think you'd have to worry much about O‐methyldopamine. Remember the study only noticed a two point reduction in people who were very likely taking gram amounts of levodopa daily.

Marsden, C. David. "'On-off' effects in patients with Parkinson’s disease on chronic levodopa therapy." Lancet (1976)
Nakazato, Taizo. "The medial prefrontal cortex mediates 3-methoxytyramine-induced behavioural changes in rat." European journal of pharmacology (2002)
McMeekin, T. L. "Apparent specific volume of α-casein and β-casein and the relationship of specific volume to amino acid composition." Journal of the American Chemical Society (1949)
 
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papaya

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@Travis my mother has slow progressing pd. she takes long acting levodopa & absolutely hates it. she takes her pill during or after her coffee. what should i tell her to do??? she goes to top pd dr. who also does research. her dr. is very open minded, but goes very by the book/medical studies. are all people with pd undermethylators? i suspect she got pd from heavy metals(she had mercury fillings removed improperly) in combo with being a slow methylator. it's sad because she used to have so much energy & no sleep issues & now she's always tired & has terrible sleep issues.
 

Travis

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3,189
@Travis my mother has slow progressing pd. she takes long acting levodopa & absolutely hates it. she takes her pill during or after her coffee. what should i tell her to do??? she goes to top pd dr. who also does research. her dr. is very open minded, but goes very by the book/medical studies. are all people with pd undermethylators? i suspect she got pd from heavy metals(she had mercury fillings removed improperly) in combo with being a slow methylator. it's sad because she used to have so much energy & no sleep issues & now she's always tired & has terrible sleep issues.
Well, green tea should prevent O‐methyldopa from building‐up. This may sound like woo but it's not: the ability of epicatechin gallate to inhibit the enzyme COMT is uncanny—if you look at the enzyme kinetic data (IC₅₀=.07·μM)—and it even works better than the drugs synthetic chemists had designed specifically for that purpose . . . and it's safer: the most popular pharmaceutical COMT inhibitors damage the liver (Entacapone; Tolcapone).

Daniel Perl was the world's leading expert in alumimum in the 1980s, and has either authored or co‐authored hundreds of articles on this dangerous ion (Al³⁺). He makes a good case that Alzheimer's and Parkinson's are essentially the same thing. Both Alzheimer's (neurofibrillary tangle) and Parkinson's (Lewy body) are uniquely characterized by their respective inclusion bodies. They are resistant to proteolysis. Experimentally‐induced Parkinson's—using the drug MPTP to reduce dopamine—is actually reversible within weeks; it takes a more resistant particle to cause a longer problem. Mercury can increase free radicals, oxidation, lipid peroxiation, and inclusion bodies (lipid peroxidation products crosslink proteins). The brain regenerates just like any body part, but breaking down Lewy bodies and neurofibrillary tangles represents a challenge. I think the best approach could be preventing their formation by avoiding iron and aluminum while eating fruit for the citrate content (known to chelate both aluminum and iron). You might think that perhaps eventually some phagocyte—such as a killer T cell—would engulf these particles and break them down. It's been shown that immune cells can cross the blood–brain barrier.

'Paradoxically, despite the presence of abundant activated microglia inthe brain of AD patients,these cells fail to mount a phagocytic response to Aβ deposits but can efficiently phagocytose Aβ fibrils and plaques in vitro.' ―Koenigsknecht

So I think even in the worst case scenario (crosslinked protein–lipid–aluminum inclusion bodies) the body has a method for dealing with it (phagocytosis). If it can happen in vitro, it should happen in vivo (how could it not?). Iron (Fe²⁺, Fe³⁺) an aluminum (Al³⁺) are the ions which
appear to be the primary cause of Parkinson's and Alzheimer's (Alzheimer's proper, and not just
hyperhomocysteinemia given a different name).

Melatonin has been shown to chelate metals, and increases at night when the the interstices relax and cerebospinal fluid perfuses the brain (this co‐incides with the lowered serotonin as the raphe nucleus begins firing at a slower rate; it starts again moments before waking). But melatonin works peripherally, like serotonin, so taking capsules delivers the highest amounts to an organ most sensitive to it (probably second or third most—arteries and the intestines do have serotonin and melatonin receptors). Folate is necessary for creating the methyl group eventually transferred to N‐acetyl‐serotonin (creating melatonin), and low‐light conditions increase the melatonin synthesis rate (light appears to actively suppress this). There can be found sporadic data that fluoride inhibits melatonin synthesis (in rats), the best evidence being a doctoral dissertation from The University of Florida.

I think the best anyone could do is to avoid iron and aluminum while letting the brain detoxify naturally, all the while taking either epicatechin gallate pills (perhaps from Amazon, perhaps from somewhere else) or drinking green tea with boron (to counteract the natural fluoride ions) to prevent the otherwise unavoidable O‐methyldopamine formed through high‐dose levodopa supplementation.

I just had an idea: Perhaps inclusion bodies are in flux; perhaps they are phagocytosed, only to release the metals to start the process all over again. There is simply no way to tell how long they exist for, and the ones viewed on microscope slides represent only one moment in time. If they can be broken down eventually in vitro, then you'd almost have to assume they also would be in vivo. Older people rarely change their dietary habits, and if
it was reversible nobody would really know. Some people are perpetually exposed to high‐aluminum water (introduced as a flocculant in city water supplies), frozen pizza (Al³⁺ both in dough (baking powder), and cheese (Na⁺[Al₃(PO₄)₈]), and iron from the multivitamin they assume is healthy.

Xie, Lulu. "Sleep drives metabolite clearance from the adult brain." science (2013)
Fournier, Isabelle. "Folate deficiency alters melatonin secretion in rats." The Journal of nutrition (2002)
Koenigsknecht, Jessica. "Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism." Journal of Neuroscience (2004)
Perl, Daniel P. "Alzheimer's disease and Parkinson's disease: distinct entities or extremes of a spectrum of neurodegeneration?." Annals of neurology (1998).
Chen, Dapeng. "Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure–activity relationship and molecular-modeling studies." Biochemical pharmacology (2005)
 
Last edited:

papaya

Member
Joined
Mar 2, 2016
Messages
305
Well, green tea should prevent O‐methyldopa from building‐up. This may sound like woo but it's not: the ability of epicatechin gallate to inhibit the enzyme COMT is uncanny—if you look at the enzyme kinetic data (IC₅₀=.07·μM)—and it even works better than the drugs synthetic chemists had designed specifically for that purpose . . . and it's safer: the most popular pharmaceutical COMT inhibitors damage the liver (Entacapone; Tolcapone).

Daniel Perl was the world's leading expert in alumimum in the 1980s, and has either authored or co‐authored hundreds of articles on this dangerous ion (Al³⁺). He makes a good case that Alzheimer's and Parkinson's are essentially the same thing. Both Alzheimer's (neurofibrillary tangle) and Parkinson's (Lewy body) are uniquely characterized by their respective inclusion bodies. They are resistant to proteolysis. Experimentally‐induced Parkinson's—using the drug MPTP to reduce dopamine—is actually reversible within weeks; it takes a more resistant particle to cause a longer problem. Mercury can increase free radicals, oxidation, lipid peroxiation, and inclusion bodies (lipid peroxidation products crosslink proteins). The brain regenerates just like any body part, but breaking down Lewy bodies and neurofibrillary tangles represents a challenge. I think the best approach could be preventing their formation by avoiding iron and aluminum while eating fruit for the citrate content (known to chelate both aluminum and iron). You might think that perhaps eventually some phagocyte—such as a killer T cell—would engulf these particles and break them down. It's been shown that immune cells can cross the blood–brain barrier.

'Paradoxically, despite the presence of abundant activated microglia inthe brain of AD patients,these cells fail to mount a phagocytic response to Aβ deposits but can efficiently phagocytose Aβ fibrils and plaques in vitro.' ―Koenigsknecht

So I think even in the worst case scenario (crosslinked protein–lipid–aluminum inclusion bodies) the body has a method for dealing with it (phagocytosis). If it can happen in vitro, it should happen in vivo (how could it not?). Iron (Fe²⁺, Fe³⁺) an aluminum (Al³⁺) are the ions which
appear to be the primary cause of Parkinson's and Alzheimer's (Alzheimer's proper, and not just
hyperhomocysteinemia given a different name).

Melatonin has been shown to chelate metals, and increases at night when the the interstices relax and cerebospinal fluid perfuses the brain (this co‐incides with the lowered serotonin as the raphe nucleus begins firing at a slower rate; it starts again moments before waking). But melatonin works peripherally, like serotonin, so taking capsules delivers the highest amounts to an organ most sensitive to it (probably second or third most—arteries and the intestines do have serotonin and melatonin receptors). Folate is necessary for creating the methyl group eventually transferred to N‐acetyl‐serotonin (creating melatonin), and low‐light conditions increase the melatonin synthesis rate (light appears to actively suppress this). There can be found sporadic data that fluoride inhibits melatonin synthesis (in rats), the best evidence being a doctoral dissertation from The University of Florida.

I think the best anyone could do is to avoid iron and aluminum while letting the brain detoxify naturally, all the while taking either epicatechin gallate pills (perhaps from Amazon, perhaps from somewhere else) or drinking green tea with boron (to counteract the natural fluoride ions) to prevent the otherwise unavoidable O‐methyldopamine formed through high‐dose levodopa supplementation.

I just had an idea: Perhaps inclusion bodies are in flux; perhaps they are phagocytosed, only to release the metals to start the process all over again. There is simply no way to tell how long they exist for, and the ones viewed on microscope slides represent only one moment in time. If they can be broken down eventually in vitro, then you'd almost have to assume they also would be in vivo. Older people rarely change their dietary habits, and if
it was reversible nobody would really know. Some people are perpetually exposed to high‐aluminum water (introduced as a flocculant in city water supplies), frozen pizza (Al³⁺ both in dough (baking powder), and cheese (Na⁺[Al₃(PO₄)₈]), and iron from the multivitamin they assume is healthy.

Xie, Lulu. "Sleep drives metabolite clearance from the adult brain." science (2013)
Fournier, Isabelle. "Folate deficiency alters melatonin secretion in rats." The Journal of nutrition (2002)
Koenigsknecht, Jessica. "Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism." Journal of Neuroscience (2004)
Perl, Daniel P. "Alzheimer's disease and Parkinson's disease: distinct entities or extremes of a spectrum of neurodegeneration?." Annals of neurology (1998).
Chen, Dapeng. "Inhibition of human liver catechol-O-methyltransferase by tea catechins and their metabolites: structure–activity relationship and molecular-modeling studies." Biochemical pharmacology (2005)
Thank you so much, you are amazing!!!
 

Zpol

Member
Joined
Apr 14, 2013
Messages
929
Age
45
@Travis , in all your great biochemistry wisdom; do you know if it would be a good idea to take a squalamine supplement with this caffeine + creatine regimen?
α-synuclein is the main protein in the Lewy bodies, so to prevent it's build up would be a good thing, correct?
Unless you know of some reason that the α-synuclein itself is preventing a brain infection of bacteria that comes from the gut.
I am looking into this as a supplement to help with SIBO-C, gastroparesis, a disfunctioning Migratory Motor Complex, and chronic microbial infection, not specifically for PD or cancer but would like to prevent them simultaneously.
I like your idea of Green Tea but it gives me serious gas and heartburn. I suppose I could try some EGCg caps.

Squalamine, a natural product studied for its anticancer and anti-infective properties, could also lead to future treatments for Parkinson’s Disease.

To our surprise, we found evidence that squalamine not only slows down the formation of the toxins associated with Parkinson’s Disease, but also makes them less toxic altogether. If further tests prove to be successful, it is possible that a drug treating at least some of the symptoms of Parkinson’s Disease could be developed from squalamine.

Christopher Dobson
A naturally-occurring compound has been found to block a molecular process thought to underlie Parkinson’s Disease, and to suppress its toxic products, scientists have reported.

The findings, although only preliminary, suggest that the compound, called squalamine, could be exploited in various ways as the basis of a potential treatment for Parkinson’s Disease. The compound has previously been used in clinical trials for cancer and eye conditions in the United States, and a trial in Parkinson’s Disease patients is now being planned by one of the researchers involved in the study.

Squalamine is a steroid which was discovered in the 1990s in dogfish sharks. It is, however, impossible to derive any medical benefits from shark tissue, and the form used by scientists is a safer and more reliable synthetic analogue. To date, it has been extensively investigated as a potential anti-infective and anticancer therapy.

But in the new study, researchers discovered that squalamine also dramatically inhibits the early formation of toxic aggregates of the protein alpha-synuclein – a process thought to start a chain reaction of molecular events eventually leading to Parkinson’s Disease. Remarkably, they also then found that it can suppress the toxicity of these poisonous particles.

The researchers tested squalamine in both cell cultures in the lab, and in an animal model using nematode worms. While their findings therefore only represent a step towards a treatment for Parkinson’s Disease in humans, they described the results as representing significant progress.

The study was led by academics from the Centre for Misfolding Diseases, based in the Chemistry Department at the University of Cambridge in the United Kingdom, and Georgetown University and the National Institutes of Health in the United States. Scientists from the Netherlands, Italy and Spain also played key roles. The findings are published in Proceedings of The National Academy of Sciences.

Professor Christopher Dobson, who is one of the authors and Master of St John’s College, as well as a Professor in the Chemistry Department at the University of Cambridge, said: “To our surprise, we found evidence that squalamine not only slows down the formation of the toxins associated with Parkinson’s Disease, but also makes them less toxic altogether.”

“If further tests prove to be successful, it is possible that a drug treating at least some of the symptoms of Parkinson’s Disease could be developed from squalamine. We might then be able to improve on that incrementally, by searching for better molecules that augment its effects.”

Professor Michele Vendruscolo, from the Department of Chemistry at the University of Cambridge and a co-author, said: “This is an encouraging step forward in our efforts to discover potential drugs against Parkinson’s Disease. Squalamine can prevent alpha-synuclein from malfunctioning, essentially by normalising its binding to lipid membranes. If there are going to be ways to beat the disease, it seems likely that this is one that may work.”

The study stemmed from research led by Dr Michael Zasloff, professor of surgery and pediatrics at Georgetown University School of Medicine in the USA. Zasloff, who also co-authored the latest study, discovered squalamine in 1993 and has since led extensive work exploring its potential as a treatment for conditions including cancer.

In the new study, the researchers explored squalamine’s capacity to displace alpha-synuclein from cell membranes – a phenomenon that was first observed in the laboratory headed by another co-author, Dr Ad Bax, in the National Institutes of Health in Bethesda, USA. This finding has significant implications for Parkinson’s Disease, because alpha-synuclein works by binding to the membranes of tiny, bubble-like structures called synaptic vesicles, which help to transfer neurotransmitters between neurons.

Under normal circumstances, the protein thus aids the effective flow of chemical signals, but in some instances, it malfunctions and instead begins to clump together, creating toxic particles harmful to brain cells. This clustering is the hallmark of Parkinson’s Disease.

The researchers carried out a series of experiments which analysed the interaction between squalamine, alpha-synuclein and lipid vesicles, building on earlier work from Cambridge scientists which showed the vital role that vesicles play in initiating the aggregation. They found that squalamine inhibits the aggregation of the protein by competing for binding sites on the surfaces of synthetic vesicles. By displacing the protein in this way, it significantly reduces the rate at which toxic particles form.

Further tests, carried out with human neuronal cells, then revealed another key factor – that squalamine also suppresses the toxicity of these particles.

Finally, the group tested the impact of squalamine in an animal model of Parkinson’s Disease, by using nematode worms genetically programmed to over-express alpha-synuclein in their muscle cells. As the worms develop, alpha-synuclein aggregation causes them to become paralysed, but squalamine prevented the paralysis from taking effect. “We could literally see that the oral treatment of squalamine did not allow alpha-synuclein to cluster, and prevented muscular paralysis inside the worms,” Zasloff said.

Together, the results imply that squalamine could be used as the basis of a treatment targeting at least some of the symptoms of Parkinson’s Disease. Zasloff says he is now planning a clinical trial with squalamine in Parkinson’s Disease patients in the US.

Further research is, however, needed to determine what the precise benefits of squalamine would be – and what form any resulting drug might take. In particular, it is not yet clear whether squalamine can reach the specific regions of the brain where the main molecular processes determining Parkinson’s Disease take place.

The researchers suggest that it would be particularly interesting to start investigating the efficacy of squalamine as a means to alleviate certain symptoms. If taken orally, for instance, the compound may perhaps relieve the severe constipation many patients experience, by targeting the gastrointestinal system and affecting alpha-synuclein in the gut.

It is also conceivable that a treatment of that sort could “cascade” signals to other parts of the body. “Targeting alpha-synuclein in the gut may perhaps in some cases be sufficient to delay the progress of other aspects of Parkinson’s Disease, at least for symptoms concerning the peripheral nervous system,” Vendruscolo said.

“In many ways squalamine gives us a lead rather than a definitive treatment,” Professor Dobson added. “Parkinson’s Disease has many symptoms and we hope that either this compound, or a derivative of it with a similar mechanism of action, could alleviate at least some of them.”

“One of the most exciting prospects is that, subject to further tests, we might be able to use it to make improvements to patients’ lives, while also studying other compounds with the aim of developing a more powerful treatment in the future.”
As far as I can tell, the actual human study is in it's infancy so it could be years before we know the results. Also, my understanding is that if α-synuclein builds ups in the gut wherever there is inflammation (which we know this happens), it could be haulted at that stage and stop from migrating to the brain. So in someone like me with chronic inflammation in the gut it would be wise to take preventative measures.
 

Travis

Member
Joined
Jul 14, 2016
Messages
3,189
@Travis , in all your great biochemistry wisdom; do you know if it would be a good idea to take a squalamine supplement with this caffeine + creatine regimen?
α-synuclein is the main protein in the Lewy bodies, so to prevent it's build up would be a good thing, correct?
Unless you know of some reason that the α-synuclein itself is preventing a brain infection of bacteria that comes from the gut.
I am looking into this as a supplement to help with SIBO-C, gastroparesis, a disfunctioning Migratory Motor Complex, and chronic microbial infection, not specifically for PD or cancer but would like to prevent them simultaneously.
I like your idea of Green Tea but it gives me serious gas and heartburn. I suppose I could try some EGCg caps.
Squalamine, a natural product studied for its anticancer and anti-infective properties, could also lead to future treatments for Parkinson’s Disease.

To our surprise, we found evidence that squalamine not only slows down the formation of the toxins associated with Parkinson’s Disease, but also makes them less toxic altogether. If further tests prove to be successful, it is possible that a drug treating at least some of the symptoms of Parkinson’s Disease could be developed from squalamine.

Christopher Dobson
A naturally-occurring compound has been found to block a molecular process thought to underlie Parkinson’s Disease, and to suppress its toxic products, scientists have reported.

The findings, although only preliminary, suggest that the compound, called squalamine, could be exploited in various ways as the basis of a potential treatment for Parkinson’s Disease. The compound has previously been used in clinical trials for cancer and eye conditions in the United States, and a trial in Parkinson’s Disease patients is now being planned by one of the researchers involved in the study.

Squalamine is a steroid which was discovered in the 1990s in dogfish sharks. It is, however, impossible to derive any medical benefits from shark tissue, and the form used by scientists is a safer and more reliable synthetic analogue. To date, it has been extensively investigated as a potential anti-infective and anticancer therapy.

But in the new study, researchers discovered that squalamine also dramatically inhibits the early formation of toxic aggregates of the protein alpha-synuclein – a process thought to start a chain reaction of molecular events eventually leading to Parkinson’s Disease. Remarkably, they also then found that it can suppress the toxicity of these poisonous particles.

The researchers tested squalamine in both cell cultures in the lab, and in an animal model using nematode worms. While their findings therefore only represent a step towards a treatment for Parkinson’s Disease in humans, they described the results as representing significant progress.

The study was led by academics from the Centre for Misfolding Diseases, based in the Chemistry Department at the University of Cambridge in the United Kingdom, and Georgetown University and the National Institutes of Health in the United States. Scientists from the Netherlands, Italy and Spain also played key roles. The findings are published in Proceedings of The National Academy of Sciences.

Professor Christopher Dobson, who is one of the authors and Master of St John’s College, as well as a Professor in the Chemistry Department at the University of Cambridge, said: “To our surprise, we found evidence that squalamine not only slows down the formation of the toxins associated with Parkinson’s Disease, but also makes them less toxic altogether.”

“If further tests prove to be successful, it is possible that a drug treating at least some of the symptoms of Parkinson’s Disease could be developed from squalamine. We might then be able to improve on that incrementally, by searching for better molecules that augment its effects.”

Professor Michele Vendruscolo, from the Department of Chemistry at the University of Cambridge and a co-author, said: “This is an encouraging step forward in our efforts to discover potential drugs against Parkinson’s Disease. Squalamine can prevent alpha-synuclein from malfunctioning, essentially by normalising its binding to lipid membranes. If there are going to be ways to beat the disease, it seems likely that this is one that may work.”

The study stemmed from research led by Dr Michael Zasloff, professor of surgery and pediatrics at Georgetown University School of Medicine in the USA. Zasloff, who also co-authored the latest study, discovered squalamine in 1993 and has since led extensive work exploring its potential as a treatment for conditions including cancer.

In the new study, the researchers explored squalamine’s capacity to displace alpha-synuclein from cell membranes – a phenomenon that was first observed in the laboratory headed by another co-author, Dr Ad Bax, in the National Institutes of Health in Bethesda, USA. This finding has significant implications for Parkinson’s Disease, because alpha-synuclein works by binding to the membranes of tiny, bubble-like structures called synaptic vesicles, which help to transfer neurotransmitters between neurons.

Under normal circumstances, the protein thus aids the effective flow of chemical signals, but in some instances, it malfunctions and instead begins to clump together, creating toxic particles harmful to brain cells. This clustering is the hallmark of Parkinson’s Disease.

The researchers carried out a series of experiments which analysed the interaction between squalamine, alpha-synuclein and lipid vesicles, building on earlier work from Cambridge scientists which showed the vital role that vesicles play in initiating the aggregation. They found that squalamine inhibits the aggregation of the protein by competing for binding sites on the surfaces of synthetic vesicles. By displacing the protein in this way, it significantly reduces the rate at which toxic particles form.

Further tests, carried out with human neuronal cells, then revealed another key factor – that squalamine also suppresses the toxicity of these particles.

Finally, the group tested the impact of squalamine in an animal model of Parkinson’s Disease, by using nematode worms genetically programmed to over-express alpha-synuclein in their muscle cells. As the worms develop, alpha-synuclein aggregation causes them to become paralysed, but squalamine prevented the paralysis from taking effect. “We could literally see that the oral treatment of squalamine did not allow alpha-synuclein to cluster, and prevented muscular paralysis inside the worms,” Zasloff said.

Together, the results imply that squalamine could be used as the basis of a treatment targeting at least some of the symptoms of Parkinson’s Disease. Zasloff says he is now planning a clinical trial with squalamine in Parkinson’s Disease patients in the US.

Further research is, however, needed to determine what the precise benefits of squalamine would be – and what form any resulting drug might take. In particular, it is not yet clear whether squalamine can reach the specific regions of the brain where the main molecular processes determining Parkinson’s Disease take place.

The researchers suggest that it would be particularly interesting to start investigating the efficacy of squalamine as a means to alleviate certain symptoms. If taken orally, for instance, the compound may perhaps relieve the severe constipation many patients experience, by targeting the gastrointestinal system and affecting alpha-synuclein in the gut.

It is also conceivable that a treatment of that sort could “cascade” signals to other parts of the body. “Targeting alpha-synuclein in the gut may perhaps in some cases be sufficient to delay the progress of other aspects of Parkinson’s Disease, at least for symptoms concerning the peripheral nervous system,” Vendruscolo said.

“In many ways squalamine gives us a lead rather than a definitive treatment,” Professor Dobson added. “Parkinson’s Disease has many symptoms and we hope that either this compound, or a derivative of it with a similar mechanism of action, could alleviate at least some of them.”

“One of the most exciting prospects is that, subject to further tests, we might be able to use it to make improvements to patients’ lives, while also studying other compounds with the aim of developing a more powerful treatment in the future.”
As far as I can tell, the actual human study is in it's infancy so it could be years before we know the results. Also, my understanding is that if α-synuclein builds ups in the gut wherever there is inflammation (which we know this happens), it could be haulted at that stage and stop from migrating to the brain. So in someone like me with chronic inflammation in the gut it would be wise to take preventative measures.

All of these proteins involved on Parkinson's and Alzheimer's, such as synuclein and tau, are microtubule‐associated proteins (MAPs). Since all more‐or‐less permanent inclusion bodies—such as lipofusin, Lewy bodies, and neurofibrillary tangles—consist of crosslinked proteins and lipids, focusing on the proteins themselves draws attention away from lipid peroxidation event and gives biochemists licence to speculate wildly on the less‐important things (you know, the fun activities). You can choose to focus on nearly any aspect of these bodies, such as the phosphorylation index of tau (τ) or the protein's final geometry. The protein τ is normally highly phosphorylated, a fact which could explain why aluminum has been shown to aggregate this MAP in vitro more than the other physiologic ions (as determined by gel electrophoresis migration, a measure of aggregate size). Even in the inorganic world, the aluminum ion (Al³⁺) has a high affinity for phosphate (although not as high as silica), which can be quickly confirmed by noting the low water solubility of aluminum phosphates. As a trivalent ion, aluminum can form three‐membered, three dimensional crosslinks—a fact which makes it useful to the hide‐tanning industry.

Microtubules are hollow protein tube sometimes covered in myelin. The insulator, myelin, consists predominately of pregnenolone and progesterone. In vitro binding data reveal microtubules to have the greatest affinity for pregnenolone, of all steroids, with progesterone usually coming in second. Although usually drawn flat, these steroids actually have a 'curl;' beta steroids are actually pringle‐shaped when viewed from the side and drawn in the more realistic chair conformation:⁽¹⁾

steroid.png click to embiggen

Besides squalamine, I think the similar pregnenolone could be useful. Coating the microtubule‐associated proteins with fully saturated lipids could stop lipid peroxidation chain reactions, and perhaps even protect phosphates from Al³⁺‐aggregation.

'Incubation of purified recombinant human tau protein with aluminum salts at concentrations ≥100 μM induces aggregation of tau that prevents its entry into SDS-polyacrylamide gels and filtration through nylon membranes. This effect is noncovalent and can be reversed by addition of EDTA. However, when incubated along with ATP, GTP, or CTP, aluminum catalyzes a covalent linkage that results in incorporation of the α- and γ-phosphates into the tau protein (phospho-incorporation).' —Abdel-Ghany⁽²⁾

The crosslinked protein–lipid complex is fairly well understood. A natural result of lipid peroxidation are aldehydes and dialdehydes such as 4-hydroxynonenal and malondialdehyde, able to form Schiff linkages with the lysine residues of proteins. This is essentially the exact thing glutaraldehyde does, the second most popular aldehyde used to fix tissues (behind formaldehyde). Glutaraldehyde works to crosslink, and some peroxidation products are dialdehydes (with crosslinking aldehyde groups on both ends). Seen in this way, the lipid peroxidation product malondialdhyde could seen as a fixative.


'Therefore, the effect of different aldehydes (glutaraldehyde, malondialdehyde and paraformaldehyde) on covalent fixation of proteins, precipitated by trichloroacetic acid in 50 μm gels, was investigated.' —Frey⁽³⁾

Do this proteins 'misfold?' Do they either hyperphosphoryate themselves spontaneously? or through an undefined mechanism? I doubt it; aluminum has strongly been implicated in the entire process, in every manner, every step of the way. But etiological explanations focused on aluminum appear to have become taboo since the '90s. Protein misfoldings from genetic polymorphisms and prions could represent the sort of pseudoscience surrounding the β-methylaminoalanine hypothesis for Guam ALS.

Aluminum has been detected in high amounts in the spinal cords of Guam residents. The ground water in Guam is characterized by a high Al³⁺/Ca²⁺ ratio.⁽⁴⁾⁽⁵⁾

Although the β-methylaminoalanine explanation is logical when viewed on certain levels, and fun to entertain, it is in fact controversial. I think anyone who examines the evidence in an unbiased manner would come to the conclusion that aluminum is primary, and that the neurotoxicity of β-methylaminoalanine is exaggerrated.

Just as in the unanimous mechanism for lipofuscin formation, unsaturated fatty acid remnants and catalytic metals (Fe²⁺, Fe³⁺, Al³⁺) are found in both Lewy bodies and neurofibrillary tangles. I think these are formative, and not a 'consequence of prions, βMAA, or genetics.' This would make the same risk factors for all three inclusion bodies: Iron, unsaturated fatty acids, homocysteine, and aluminum perhaps being the four most significant.

The molecular composition is the inclusion body, physically, and they simply wouldn't be inclusion bodies without their enzyme‐resistant crosslinks.

[1] Moss, G. P. "Nomenclature of steroids (Recommendations 1989)." Pure and Applied Chemistry (1989)
[2] Abdel-Ghany, Mossaad. "Aluminum-induced nonenzymatic phospho-incorporation into human tau and other proteins." Journal of Biological Chemistry (1993)
[3] Frey, Manuela D. "Rapid staining of proteins in ultrathin‐layer isoelectric focusing in polyacrylamide gels." Electrophoresis (1982)
[4] Perl, Daniel P. "Intraneuronal aluminum accumulation in amyotrophic lateral sclerosis and Parkinsonism-dementia of Guam." Science (1982)
[5] Yoshimasu, Fumio. "Studies on Amyotrophic Lateral Sclerosis by Neutron Activation Analysis‐2. Comparative Study of Analytical Results on Guam PD, Japanese ALS and Alzheimer Disease Cases." Psychiatry and Clinical Neurosciences (1980)

 
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