Compounds that prevent a-syn misfolding

[zawy]

This is a list of the best compounds with the ability to reach the human brain and have been shown in test tube or animal research to slow or stop the accumulation of misfolding a-Syn. The first 4 have the added evidence that they work in humans by epidemiological studies. Most of the other compounds listed do not have epidemiological evidence because they are not consumed in large enough quantities, not because they are less effective. There is every good reason to believe most of these slow PD in humans.

This is not all the compounds that help PD. There are many others that alleviate symptoms, reduce inflammation, chelate iron, cause neurogenesis, improve mitochondria function, and reduce oxidation. This also does not include basic RDA nutrients that have also been shown to result in less PD in humans (vitamins A, D, B's, magnesium, and zinc).

Most people do not have the time, ability, and/or desire to really go through this list, let alone take more than 3 of them, so isolating what is best is important. My main point is to show PD research is extensive and succeeding. Most of this research in a-syn misfolding for these compounds has occurred in the just the past 3 to 5 years.

Also shown in human epidemiological work

========================

caffiene

nicotine

Black tea (maybe the gallic acid that may not be present in the extracts)

EGCG (green tea extract)

grape seed extract (gallic acid)

Myricetin (in many plants)

Morin (orange, guava)

apigenin (parsley, celery, chamomile, dandelion)

baicalein (skullcap, a purple flower plant, powerful but appears to not make it to brain)

Nordihydroguaiaretic (a stilbene, may not absorb)

specific citrus compounds: naringin, tangeritin (expensive), HMF, morin, auraptene (VERY expensive)

less likely in one good paper, but still very possible

========================

Ginkgolide B (ginkgo)

Genistein (ginseng)

olive oil (ellagic acid)

Quercetin (e.g. apples)

Non-plant compounds

===============

nilotinib (pharmaceutical, primarily by increasing AMPK)

rasagiline (pharmaceutical)

methylene blue (common chemical, not completely safe)

4-phenyl butyrate (BPA)

rapamycin

fisetin (in strawberries, reduces a-syn expression, not exactly its misfolding directly)

myricetin: vegetables, fruits, nuts, berries, tea, and is also found in red wine. Structurally similar to fisetin, luteolin, and quercetin and is reported to have many of the same functions as these other members of the flavonol class of flavonoids

references to FULL text articles:

ncbi.nlm.nih.gov/pubmed/226...

ncbi.nlm.nih.gov/pubmed/182...

ncbi.nlm.nih.gov/pubmed/214...

rasagiline, methylene blue, BPA, baicalein

sciencedirect.com/science/a...

nicotine

ncbi.nlm.nih.gov/pubmed/128... (full)

nicotine and caffeine

ncbi.nlm.nih.gov/pubmed/250...

Grape Seed Extract (gallic acid)

ncbi.nlm.nih.gov/pubmed/241...

ncbi.nlm.nih.gov/pubmed/192... (full)

ncbi.nlm.nih.gov/pubmed/206...

naringin and rutin

ncbi.nlm.nih.gov/pubmed/223...

tangeretin (tangeritin)

ncbi.nlm.nih.gov/pubmed/231...

ginseng

ncbi.nlm.nih.gov/pubmed/243...

ellagic acid

ncbi.nlm.nih.gov/pubmed/252...

heat shock proteins (hot baths and exercise)

ncbi.nlm.nih.gov/pubmed/159...

[Sunnysky]

Hi Zawy thanks for going to the trouble to inform us of all the info in your last post I'll wade through all the links in time thanks again for your effort

Cheers Sunnysky

[paddyfields]

Thanks for thiis

[BillDavid]

A perspective, relative to my understandings. As I understand the assumed problem with alpha synucleon, is that it is misfolded, to form prions, which are thought to cause the damage to the dopamine producing nerve cells. I read the bottom abstract. It did not mention alpha synucleon, miss folding proteins, prions, or Parkinson's Disease?

BillDavid

[zawy in reply to BillDavid]

I was editing my notes and HSP was thrown into the bottom because I did not want to forget that HSP's escort misfolded proteins out of the cells. I do not know off hand if they prevent misfolding. Being able to escort misfolded proteins out of the cell could regain some function in addition to preventing further damage, or it might help spread the disease because getting it out of the cell might lead to it entering other cells. I assume HSP's help more than hurt because exercise and outside work mean less PD. I have not researched HSP's in regard to PD.

[BillDavid in reply to zawy]

Zawy

About protein folding, my understandings, protein folding forms prions, miss folding ( changing shape)produces bad Prions, leading to bundles or aggergates. Proteins with poly glutamine sequences are thought to cause miss folding. The reason is the identification of genetic component for Huntington disease, that is 39 or more units of the codon replicant CAG., each of which triggers polyglutamine formation.

This genetic cause is identified in Huntington diisease. It is assumed that there is a similar genetic component for Parkinson's and other protein folding diseases including Creutzfelt-Jakob Disease and Chronic Traumatic Encephalopathy (associared with NFL head injuries and some cases of PTSD? At this point, the genes (such as PINK) that have been identifed with PD, are not involved in Protein folding and associated with early onset PD. The other diseases mentioned are all wasting diseases. fortunately PD is not. Leads me to wonder if PD fits the pattern? My understanding is that protein formation and folding are thought to occur at the Epigenetic level of functioning?

Regards, supplements, which I have taken, they are usually assoicated with some kind demographic observation, such as PwP tend to have lower levels of vitamin D3, the assumption is that higher levels of D3 are preventative, It is also understood that PD involves an immujne response which is assoicated with inflamatory overactivity and excitotoxicity. This involves microglia cells which have immune function such as secreting cytokines, etc. Manys upplements are thought to impact this system, for example, N Astyl L Cysteine (NAC)

increses brain levels of glutathione which is low in those with PD.

Curcumin is thought to be antiinflammatory, reduce micrglia cell activation.

Zawy, expect that the cure for PD, will be found in its pervention. which while being a miracle, would not impact those of us with PD, any more than piolio vacinne helped those who already had the disease.

Recommend reading Chapter 7 in Norman Dodge's MD latest book.

BillDaavid

[zawy in reply to BillDavid]

I am sure there must be genes that make one more susceptible to misfolding that results in PD. Genes are the dominant factor in only about 10% to 15% (misfolding or not), so yes, non-genetic factors dominate. A-syn misfolding apparently occurs and spreads in in the brain in all populations. Clearly pesticides cause it to initiate, as well as (probably) viral or bacterial, bad nutrition, and trauma.

All the above indicates there's every reason to believe optimal nutrition can stop it from getting worse.

Exercise and some nutrients are known to cause neurogenesis, more than people believed in the past, but I do not have a lot of hope for replacement of dead neurons except by stem cell injection which appears to have phenomenal results.

By reversal of symptoms other than this I am referring to three methods:

1) dopamine, serotonin, and melatonin replacement.

2) repair of cells that have a-syn aggregates causing decreased capabilities, but are not yet dead cells.

3) heavy use of the remaining neurons so they can get stronger and take over for where old ones have died

So I hope it was not better sugar control or 5-HTP that reversed my tremors, but one of the compounds I take to revert the damage to cells that are not-yet dead. That is my hope; that the reversal of tremor is the result of better functioning cells that should indicate at least a partial slowing down of progression.

I had recently "redoubled" my efforts because my tremor and mood has been substantially worse than it was 10 months ago, when I first noticed the tremor and started taking videos of it. It appears something worked, and I hope to stop it 100% and get my sleep and mood back to where it was 5 years ago. There is a lot of money in "balance clinics", so I believe I can improve it also. I don't know if short term memory can be regained.

I have no hope for my smell neurons. My smell started disappearing a lot about 15 years ago when I was getting sick all the time from not getting any vitamin D at all. That's why I strongly believe a lot of PD is caused by cold/flu viruses.

[BillDavid in reply to zawy]

email me at [[e-mail]]

BillDavid

[johntPM]

Thanks for this list. A research group in Iran has written several papers reporting that cuminaldehyde reduces alpha-synuclein fibrillation. This is based on in vitro experiments. Cuminaldehyde is found in cumin.

John

[zawy in reply to johntPM]

That's a really good find because the molecular weight of cuminaldehyde is only 148, which is a lot less than all these other compounds that are able to cross the blood-brain barrier, so it should cross. Now the question is does it make it through the intestines and past the liver's glucuronation? It is oxidized by one of the liver's P450 enzymes, but I do not know which one so I do not know if grapefruit or peperine could block it's degradation. It does not appear anyone knows if it can make it past the liver and therefore to the brain.

A way to take a guess about its bioavailability and even brain-availability is to look at what traditional medicine says. Especially if it has noticeable mental effects. "Āyurveda and Siddha regard jeeraka [Cuminum cyminum ] as having a bitter taste with a hot property, capable of removing vāta and kapha doṣas but causing pitta. It is dry, astringent, appetising, digestive, strengthening, light for digestion, good for the eyes and an aphrodisiac. It is used in the treatment of indigestion, dysentery, enlarged spleen, flatulence and vomiting."

Here's the paper you're referring to:

ncbi.nlm.nih.gov/pubmed/263...

It's about 1% in light colored cumin seed and half as much in black cumin. It's the ingredient that gives cumin its flavor. It's about 30% in cumin essential oil. It's the primary aldehyde.

It is not available as a supplement. It would take 2 heaping teaspoons cumin to get 100 mg cuminaldehyde which is minimum dose for most of these supplements, except for nicotine (people getting only 50 mg from a pack a day are strongly protected against PD, although 3 packs in one study wa a lot better). 6 cups of coffee is better than 3 cups and that's 600 mg of caffeine. The response in animals is almost always dose-dependent. You can't just take a supplement. It has to be in a strong dose.

It also prevents oxidation of L-DOPA, is antidiabetic, and protects against superoxide oxidation.

ncbi.nlm.nih.gov/pubmed/115...

ncbi.nlm.nih.gov/pubmed/147...

ncbi.nlm.nih.gov/pubmed/839...

ncbi.nlm.nih.gov/pubmed/157...

[racerCP in reply to zawy]

Not much of this makes sense. Little evidence that PD is a vitamins or substance induced disease like scurvy or rickets. It affects most people of virtuous lifestyle and habit. I have exercised all my life, eaten vegetables galore and taken supplemen and I am a parkie.. I am sure most of us has been the same. Just hope the mystery is solved.

[zawy in reply to racerCP]

The compounds I've listed are for correcting a disease, not for correcting a deficiency. I use them like pharmaceuticals. There's just better scientific evidence for what I've listed than there is for most of the pharmaceuticals being prescribed for PD.

Eating good did not protect you against PD. Berries, apples, and strawberries protect men, but not women.

Virtuous lifestyles are a primary cause of PD. A heavy-smoking, moderate beer-drinking, high cholesterol, heavy-coffee-drinking, shirtless construction worker with a rich diet is very strongly protected against PD, especially if he laughs at serious people and avoids chocolate and milk and happens to be getting enough magnesium and not too much iron. Farmers, teachers, pastors, and desk jobs are more likely to get PD.

It has been known for about 100 years that honest, honorable, reliable, hard-working, serious people are more likely to get PD. Rich diets (high uric acid) are strongly associated with less PD.

Chocolate, milk, low vitamin D, low magnesium, manganese (not magnesium), pesticides, and iron are associated with higher incidence of PD.

What I write may not make sense to some readers, but it does not mean it is not true.

[zawy]

for those following this thread, see my new post:

healthunlocked.com/parkinso....

[oceanflower]

Thank you for sharing your research, Zawy. I'm new here on this site, (3 years ago diagnosed) and feel I've hit a goldmine of info reading your posts. Are you a doctor perhaps? Or a scientist? I'm very impressed by your knowledge! I've been reading your info every morning for the past week with my neuro-protective coffee. Merci!!

[zawy in reply to oceanflower]

I graduated in electrical engineering, worked in environmental science, and made money from selling stuff for health. I'm definitely a scientist. I can keep up with the medical literature except for when they get too deep into the molecular biology. I've studied nutrient-based health stuff more than anything else.

[oceanflower in reply to zawy]

Interesting background you have! I really appreciate reading your posts. You have a good handle on the research it seems - must be hard to fit in working at the same time. Thanks to you, I'm off to buy some turmeric, or cumin or both? Not sure what is best. Hopefully the health food stores in my city (Vancouver) will have the right kind.

[zawy in reply to oceanflower]

I am not sure either does anything. I was posting about turmeric to show how people should be able to make making nearly as good as the expensive stuff, but I still have no information that enough will get to the brain. I have not researched cumin enuogh to recommend it. My "recommendations" are below.

[earthdweller]

This is very interesting. It'll take me a while to wade through all the science bits as I'm not a scientist. But does this mean that we should all start smoking and drinking more tea and coffee? (I'm happy to do the last two, not sure I want to take up smoking at this stage of my life!)

[zawy in reply to earthdweller]

I can only give advice to "the average person with Parkinson's", which means it may not apply in any particular case, in order of importance, with a lot of guessing except for #1, #2, #3:

1) Exercise, 1 hour in morning, 1 hour in evening, heart rate > 120 BPM.

2) rasagiline if your Dr determines it is appropriate in your case (nearly all new cases)

3) black tea extract, as much as possible. I do 6 pills per day

4) melatonin if sleep is not deep, up to 20 mg/day if needed as determined by experiment on yourself

5) magnesium, vitamin D, vitamin E, B-complex, zinc

6) 1/3 cup coffee grinds (6 tablespoons) in 16 oz coffee in the morning (6 cups coffee equivalent)

Foods: grapefruit if it does not interfere with your medications (otherwise any other citrus), 1 beer per day, olive oil, canola oil, blueberries, broccoli, apples, strawberries, kale, spinach.

For serious cases, go out of country if you find a reliable place that can do stem cell implants for PD. This is injecting something into the very center of your brain, so you want to be sure of their proven experience.

I'm currently researching each of the compounds in my original post to determine which ones are most likely to reach the brain. It takes about 1 day each. Bioavailability is hard to determine. For example, in 2004 they discovered oxidized baicalein is incredibly good at breaking up existing a-Syn problems, not just preventing it from forming. Unfortunately, it does not seem possible to get it past the liver and into the brain.

[earthdweller in reply to zawy]

Wow, thanks Zawy, that's very interesting. So is black tea extract better than just drinking black tea? Also I don't get no. 6, about the 1/3 cup coffee grinds in 16 oz coffee. (Coffee in coffee? Maybe I'm just being slow, not sure..)

I can see that it's important to get a wide selection of vitamins. Unfortunately they always have a harsh effect on my stomach when I take them.

I'll take a look at the studies you've linked to in your post above. I assume this is where your information has come from? All very interesting, thanks for sharing this.

[zawy in reply to earthdweller]

My recommendations are not based on just this post, but a lot more.

I do not know if black tea extract is better than black tea. I've started doing both. It might be the gallic acid that seems to make black tea better than green tea, in which case the plain tea might be better. I do not know if the extract keeps the gallic acid.

I boil 10 oz water, toss in 1/3 cup coffee, and strain into 6 oz cold water. That's 6 equivalent 8 oz cups of coffee in 16 oz. A little over a tablespoon is the amount of coffee grinds in an 8 oz cup. The first few times it was pretty strong and kept me awake, but now I seem adjusted to it. With this I take 2 black tea extract pills, 2 green tea extracts, 2 grape seed extracts, calcium carbonate, and magnesium. This is just below my level of nausea when not taken with food.

I am currently using 4 tea bags in 16 oz. I think 20 tea bags per day would be a good and serious treatment level for PD. Dose is every thing, in most things like this. 10 tea bags per day is likely to work only half as well.

Zinc and green tea extracts need to be taken with food. Especially Zinc when it comes to nausea.

[Raissakagan in reply to zawy]

Hi Zawy,

I thought that drinking strong black tea increases tremor.

That's the reason why I stopped drinking tea and coffee before gym.

20 bags a day seem to be quite a lot.

Did you notice it affected your tremor?

[zawy in reply to Raissakagan]

I've since found out the good study on black tea was in Singapore, where they also have a strong connection between mercury and PD and eat a lot of fish food. Both looked like good studies. Then I found out black tea helps make the methylmercury in fish less absorbable. So there is a possibility black tea may not be a world-wide benefit to PD. However, I continue to take it, but certainly I can't handle 20 bags a day as well as 6 cups of coffee. I am sticking with 4 to 5 bags in 2 cups. The effect on sleep is the main thing, but maybe caffeine tolerance could be built up. As far as the increased tremor, I believe that will be only an essential-type of tremor that is not related to the PD directly. I mean if it increases tremors, I would not consider it as causing harm to the underlying problem. I also take nicotine which is also one of the 3 strongest protects against developing PD (magnesium in sparse data seems to be the other...i recently made a long post about that). The nicotine makes my balance worse for sure, but in no way do I believe it is making the underlying condition worse. I have not noticed a problem from tremors and tea, but I do notice a problem when I am in starvation mode, which has protective benefits to the brain, usually, but if diabetes are blood-insufficiency is an underlying cause of the PD, then the lack of food, oxygen, or blood to the brain can be causing cells to die, if not cause the a-syn misfolding to get worse.

[jens667]

I live in Berlin, Germany and want to thank you for this highly professional post! I've done extensive research on the disease-modifying effects of d-beta-hydroxybutyrate which basically is a ketone-body build when you are on a ketogenic diet. Are you familiar with the publications on the effects of the ketogenic diet in neurodegenerative diseases?

[zawy in reply to jens667]

I was not able to confirm benefits of ketogenic diet in Parkinson's, except that when fasting uric levels are higher and uric acid is known to be of great benefit. I have not researched hydroxybutyrate. I have a theory that PD is a lot like cancer and that both might get worse with more simple carbs in the diet. I think there is a correlation between PD and more carbs, and olive oil is protective. But I did not see anything directly in regards to ketogenic diet that made me see a firm and direct connection.

[jens667 in reply to zawy]

This might be of interest to you (for a beginning):

ncbi.nlm.nih.gov/pubmed/195...

ncbi.nlm.nih.gov/pubmed/108...

there is a lot more.

[zawy in reply to jens667]

Thanks. I'm a big believer in ketogenic diets and I've suspected it should be very beneficial for bypassing and supporting impaired mitochondria in PD. I don't know why I never really looked into it. Maybe because like a low-calorie diet, I just assume it is good for the brain. So rather than looking at mice research, I went straight to epidemiological work to see if my suspicions were correct, and nothing jumped out at me, except high carbs might be bad. But I knew ahead of time it was not likely to be something a big study had uncovered.

[zawy in reply to jens667]

I assume ketogenic diet does not need complex 1 in the EEC to produce energy. Complex 1 is impaired in PD. I believe "sugar" usage in PD takes an inefficient anaerobic energy producing path. There is a big theory that a lot of cancers are caused by sugar taking the anaerobic path. I believe an impaired complex 1 causes this in PD if not a lot of cancers. So I believe a major benefit from a ketogenic diet may be simply from preventing sugar from using the anaerobic path. With only sugar and fewer ketones, he cells will think they have plenty of energy because they somehow see a lot of sugar coming in, but then they do not get enough energy to support themselves because it's not taking an aerobic path, so they die. Flooding the brain with oxygen during exercise thereby helps whatever valid complex 1's are remaining to carry the missing energy load. Likewise ketogenic diet provides another path for sufficient energy, not letting the faulty complex 1's cause problems.

[Raissakagan in reply to jens667]

I tried ketogenic diet for PD and it had a serious negative impact . I still haven't recovered from it. Though I realise every one is different.

[zawy in reply to Raissakagan]

In my previous post to you above, I gave an explanation as to why I think dieting could be harmful, even though it is generally good for the brain. People have notice alcohol or a sudden good dose of food stops tremors in the short term. About 50% of PD cases seem to have some extent of undiagnosed mild diabetes. I consider it a partial cause of some PD. Ketogenic diet is supposed to be good for diabetes. But impaired cells may not be able to use the ketones as good as sugars, if they are dependent on the anaerobic method of generating energy as a result of being partially damaged. Cells that were impaired could have been sped up in their dying process. This is the opposite position of what I said above, where I hoped ketones could help those same cells more by bypassing the fermentation (which occurs due to impariment. So your experience is important to me for keeping an open mind as to if a ketogenic diet is good or bad. The one thing I continue to be convinced of is that more oxygen to the brain is good, because because aerobic respiration will generate more energy per sugar molecule for those cells to function and heal. More energy helps prevent misfolding of a-syn. And if the underlying cause of the PD is vascular insufficiency or diabetes, more oxygen is good. This could be the primary reason exercise helps. I'm getting a CPAP machine for trying to get longer sleep, and maybe an oxygen tank for when I first wake up in the morning. I'm pretty messed up the first thing in the morning. My theory is that it is from less breathing (oxygen) at night, and that PD might suppress the breathing response like it does the thirst and many other responses. Due to the lack of norepinephrine connection in the locus ceurulus damage that may suppress certain sympatheic system ressonses, I might try wellbutrin, for the same reason Prozac can help compensate for less serotonin, and melatonin because there are fewer melatonin receptors.