Parkinson's Movement
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Molecule capable of halting and reverting neurodegeneration caused by Parkinson's disease identified (False Hope or a real good News? )

The small SynuClean-D molecule interrupts the formation of the alpha-synuclein amyloid fibres responsible for the onset of Parkinson's disease, and reverts the neurodegeneration caused by the disease. The study headed by UAB researchers was published in PNAS.

uab.cat/web/newsroom/news-d...

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Looks very interesting. There’s a lot of talk about the alpha synclein molecules and that’s what mannitol is meant to help get rid of I think

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Yes. Mannitol seems to help dissolve plaques that have formed and may prevent future folding. Readily available at a low cost, you have the choice to take the plunge and be your own N of 1 human experiment without waiting for a new expensive drug to be developed to achieve the same result. My husband took the plunge almost two years ago followed by Allithiamin last year and he just seems to be gradually improving in subtle ways as time goes on. Considering he was diagnosed 14 years ago, the extent of his improvement to many seems like a miracle. He is 82 and still drives himself to work.

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Wow, that's impressive.

What made you use Althiamine. Is your husband on any prescription meds? Thanks

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Actually is it Allithiamine 50 mg. which is a fat-soluble form of B1 or Thiamine. I heard about its use on this website and decided to try it to see if it would help my husband's problems with gait and balance. It's a long story--after all, he is 82. The only meds he takes is LDN (low dose naltotrexone), synthroid 37.5 mcg and Carbodopa/Levodopa 10/100. He only started on the C/L in December 2016 and it helped significantly. Then I heard about Mannitol and he started on that gradually and got up to the recommended dose in February 2017 and kept seeing more improvement over time. He didn't want to increase the dose because he was satisfied where he was and wanted to be able to get off meds if he wanted. (He tends to be medication adverse. He's had some bad reactions in the past including nearly dying from anaphylaxis (sp) shock from Penicillin). I am a nutritionist by profession and we are both inclined to experiment with natural supports for health issues. Bear in mind, everything is not perfect but compared to all the crisis our friends of similar age seem to be experiencing, he does very well. We have a good life and are very grateful for all of our many blessings!

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What is the recommended dose for mannitol and at what dose did your husband begin? I started mannitol last week and have been taking one teaspoon full in an eight ounce glass of water, but I think it's too much....upset stomach...

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The ideal dose is based on weight. Go to the website, join the registry and take the survey and they will give you your ideal dose. By doing the survey on a regular basis, you become part of an informal study on how mannitol may impact PD progression and symptoms.

Mannitol as a sugar alcohol can cause gas in some people and loose stools. We started at about 1/8 of the recommended dosage 2X/day in tea or other beverage and increased to the recommended amount over 4 weeks. If you experience undesirable symptoms you can go back to the lower dose where you did't have any and give your body a little longer to adjust.

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Could you elaborate on the website please? Thanks

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clinicrowd.info/parkinsons/ is the website for mannitol

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Thank you!

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clinicrowd.info/parkinsons/ is the website for mannitol

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Thanks!

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Hi Jim I’ve always had trouble getting into the clinicrowd website. I looked up my notes and a 70kg individual takes 10 grams(1 tablespoon) . I take a heaping teaspoon in my tea. I had to do the conversion since we don’t use the metric system (we learn it but I dont remember any of it!!) Just in case you have any trouble accessing the site.

Connie

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Try syncolein.com has anti-gas agent

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Hello Answerseeker

I see your husband takes synthroid 37.5 . Is he tremor or non-tremor dominant? I am asking because I saw this study that links non-tremor pd to low free t3 :

ncbi.nlm.nih.gov/pubmed/259...

Thank you and congratulations on great results with your spouse! Encouraging to see this kind of results!

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Thanks. We are very grateful. In working with clients I often see dramatic improvements no matter their health concern from encouraging people to pay attention to the basics: adequate hydration, sleep, moving more, eating real food (organic and Non-GMO as much as possible) and taking time daily to just be and have FUN. From there the detective work begins to address complaints that still remain.

My husband is tremor dominant and that is the one symptom that in fact seems to be getting a bit worse. He has an appointment with his GP this afternoon and one of the things I want to bring up is to do more complete Thyroid work up and reevaluate his dose of Synthroid to make sure he is not on too high a dose. Theoretically, perhaps the use of Allithiamine could lead to better endocrine function.

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My husband is also tremor-dominant. He had total thyroidectomy 8 years ago. His surgeon started him on Synthroid, but ever since, his free T3 was never normal range. The doctors upped and lowered his Synthroid several times over the years. Finally, after reading and searching T4/T3, I realized that, just like any conventional meds prescribed by medical doctors, my husband never achieved the ideal T3 levels. My husband had a thyroid test prescribed by our alternative doctor. His T3 was barely above the normal range. The alt doctor recommended Armour Thyroid or Nature Thyroid, natural thyroid hormones. Our medical doctor didn't want to prescribe it but our compounding pharmacy pharmacist suggested add on T3. The pharmacist compounded T4/T3 hormones and that's what my husband started 3-4 days ago. We are going to wait to see if his T3 improves, if not, we will definitely go Nature Throid!

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Anywhere I am referring to T3 above, I am referring to FREE T3.

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Hello Despe,

Can I ask you to keep us posted on your husband's results on T4-T3 and if you give Nature Thyroid a try further along?

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I sure will, Parkie. Thyroid problems are worse than PD!

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Hello Despe

Thank you for your reply.

How are thyroid problems worse than PD's?

Thank you

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Symptoms are very similar to PD. No energy, brain fog, joint pain and if left untreated one can go to shock and die--that's for starters. No life without thyroid hormones.

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Despe,

Since symptoms are very similar, do you sometimes think he might not actually have PD? (only thyroid)

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Oh, yes. Many times, but Hypothyroidism lacks rest tremors although I believe there is some shaking involved in Hypothyroidism.

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I tried all of these myself, all had failed for the past 10 years+. Back to T4 now.

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Did you have total thyroidectomy? I am sorry your thyroid hormone replacement failed for you. Did you ever have T3 added to T4? The one my husband is taking now was compounded by the pharmacist. Hope it will work better than Synthroid, the conventional med.

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Yes, I tried all avenues. I read all the books. I still have the thyroid glands but it stopped working. I also tried pig thyroid, which worked for a while but it stopped working after that. Wishing you all the best of luck.

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Despe, Ask your husbands doctor to do Free T4, Free T3 and Reverse T3 (RT3) levels. I am a medical doctor treating mainly Thyroid related patients. I prefer Free T3 in 60-70% range and RT3in 20-30% range. If these ranges are reversed then you need to be on T3 meds only till range is improved. I have more information on my website: ThyroidSecondOpinion.com. If you need any help, please do not hesitate to let me know. Wish your husband 'A Very Good Health'.

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Thank you! Are you a doctor with PD? Actually, this coming Tuesday, he has an apt with the endocrinologist. I will extract the information and show it to him.

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hhshahmd,

I am curious if you are using high dose B-1 in your practice and if so, what are you using it for?

Art

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I communicated with Dr. Constantini and he sent me not only protocol but lots of other information. I am now trying B1 for Chronic Fatigue and Fibromyalgia also. It is too early (just few weeks) to know the results. He advised me to start low dose (like 50 mg. twice a week I/M) and then gradually increase it. Will update as I see results.

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That will be very interesting to hear about. I look forward to your updates! Those are very low starting doses compared to what is used on this forum and by Dr. Costantini, but starting low and working up slowly also seems to have the advantage of greatly reducing the potential for unwanted side effects.

Dr. Costantini is quite generous when it comes to sharing his information and time about B-1 and he is a great human being!

Art

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thyroidsecondopinion.com has expiredWebmaster please contact Hostgator.com

No such site.

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Thank you for your reply. I might try Allthiamine, as Thiamine did not work for me.

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I do not believe. Sounds like an ad. Sorry!

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An ad for what? I'm not selliing anything. :)

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How much of each does he take;is he on meds ?

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see response to Kerrington.

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How much Alithiamine does he take? Thanks

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If I’m not mistaken Roy first was taking Allithiamine twice a week before b1 . I tried it for awhile but then switched to thiamine hcl when Roy had better results with that correct me if im wrong. Does he take allithiamine daily?

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Before b1 hcl

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Yes, once a day. Tried adding a second and his symptoms got worse so went back to one. Actually bought Thiamin HCL 500 mg and was corresponding with Dr. Costantini and had asked before Art started how he determined when you reached the right dose. He said it is based on the "Pull" test that neurologists typically do during an exam. I noticed during exams, his not only his pull test but all the other typical reflex tests done seemed good as an observer. We made another appointment with a new Movement Disorder Specialist he is now going to and he confirmed this was so. We decided if it is not broken, no need to fix and did not proceed with the Thiamine HCL. The doctor's comment was very interesting and typical of American docs. When I shared with him places he could find info on Mannitol and Dr. C's work with B1, he said, "Although these things (and others we do) may work for my husband he could not recommend them because there wasn't enough research to show they work for the general population and not just a small subset of individuals." He was pleased that my husband was doing as well as he is.

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Thank you answerseeker!!😊

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We're is mannitol available and in what fo

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I'm curious. Anyone else out there who's been taking mannitol who can give feedback on their experiences with it? I'm sure a lot of us would like to hear more and would appreciate it.

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See my profile regarding mannitol i get from syncolein.com run by Don Mccammon an ex doc with PD. He adds anti-gas agent to mannitol to settle tummy

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Here's a link to the abstract. Full text costs $10.

pnas.org/content/early/2018...

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Thanks a lot, Iqbaliqbal.

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What compound is it? Can we buy it?

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The actual molecule is shown on page 14 of the supplemental data:

pnas.org/content/pnas/suppl...

It is actually a relatively small molecule and so has the potential to get past the blood-brain barrier. Interesting work. These things take time, so chances are it will be a couple of years until they have good human data. So far so good with this one, at any rate.

On a hunch I compared it to the chemical structure of thiamine:

google.com/search?q=thiamin...

and there is a remarkable similarity. Both molecules have two rings one of which contains nitrogen, and a nitrogen sidechain. I think the inventors are being little too cute to call this Synuclein-D. They could just as well call it a patentable modification of thiamine.

Be all that as it may this work provides interesting insight into the possible mode of action of thiamine.

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Park Bear,very interesting point here, you have a brilliant intuition. Thank also to Iqbal for sharing this! Gio

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"After analysing over 14,000 molecules, they found the SynuClean-D molecule, which inhibits the aggregation of the alpha-synuclein protein and breaks the already formed amyloid fibres, thus preventing the initiation of the process causing the onset of the neurodegenerative Parkinson's disease."

This is an extract of the article published above by Iqbal, I wondered if of all these thousands of substances tested had also tested the thiamine or have thought not to do so? I would have done it and also for other vitamins.

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They used the term "analysing" so this was probably done by computer before they started lab experiments. Be that as it may, I agree testing vitamins would have been in order.

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I don't see any similarity to Thiamine. Those are very different molecules.

A) Synuclein-D : 2-hydroxy-5-nitro-6-(3-nitrophenyl)-4-(trifluoromethyl)nicotinonitrile :

C13'H5'F3'N4'O5 chemspider.com/Chemical-Str...

B) Thiamine hydrochloride :

C12'H18'Cl2'N4'OS chemspider.com/Chemical-Str...

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What improvement has he had on allithiamine? Any rigidity improvement ?

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SYNUCLEAN-D has been shown to stop the degeneration of dopaminergic neurons in both in vitro and in vivo models, thanks to its capacity to inhibit alpha-syn aggregation.

Level of Innovation

In contrast with other alpha-syn aggregation inhibitors that are already on clinical trials, SYNUCLEAN-D has the unique ability to block alpha-syn aggregates, prevent them from propagating and help to disrupt and clear these inclusions. To date, there is no other reported chemical compound that offers all these features in a single molecule.

caixaimpulse.com/projects/-...

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The natural flavonoids BAICAILEIN and SCUTELLAREIN turned out to be equally superior in the inhibition and disaggregation of a-syn fibril formations ncbi.nlm.nih.gov/pmc/articl... Both are excellent inhibitors, completely inhibit synuclein fibril formation after 3 days incubation.

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

Personally I believe what is worth mentioning is their study on the a-syn screening methodologies and their more sensitive approach able to identify smaller fibril formations and produce faster in bulk screening results.

However in their preliminary study “High-Throughput Screening Methodology to Identify Alpha-Synuclein Aggregation Inhibitors” researchgate.net/publicatio... The SynuClean-D (molecule 2-hydroxy-5-nitro-6-(3-nitrophenyl)-other 4-(trifluoromethyl)nicotinonitrile ) exhibited medium inhibitory effect of 32% compared to other compounds which exceeded 70% inhibition.

Regarding their in-vivo study, the structure of a simple biological life-form such as a worm, has almost no resemblance to the structure and chemistry of the human brain. It would be more meaningful if they performed their in-vivo study in a more advanced life-form , such as a Rodent, which is known to exhibit PD-like behavioural features mainly by using rotenone to destroy the dopaminergic neurons in their brain. Besides, there are thousands of compounds that proved effective on simple or advanced life forms and failed to show any substantial benefits in humans studies or failed to established a safety profile .

What really concerns me is whether they screened for potent natural compounds, such as certain Flavonoids, which have proved in multiple in-vitro and in-vivo studies that they exhibit superior inhibitory effect and brain penetrating properties. Surprisingly their published table of “Representative active compounds identified in the high-throughput screening” mainly includes lab-made compounds with questionable safety profile.

Studies ncbi.nlm.nih.gov/pmc/articl... showed that Flavonoids with three or more vicinal hydroxyl (OH) groups exhibit potent inhibitory effects on α-synuclein fibrillation.

The flavonoids BAICAILEIN and SCUTELLAREIN (HP-6) include 3 vicinal hydroxyl (OH) groups. Those are some of the most potent a-syn inhibitors in the nature able to almost completely, at least in-vitro studies, cleared-up fibril formations and inhibit a-syn aggregation.

Other potent 3 vicinal-HO flavonoids include MYRICETIN, EGCG CATECHINS, TRICETIN, ERIODICTYOL ncbi.nlm.nih.gov/pmc/articl...

Flavonoids neuroprotective effects can be related a) indirectly, to their ability to modulate cell-signaling pathways b) directly, to the ability to bind and disintegrate a-syn protein aggregations c) the antioxidant properties of flavonoids in combating oxidative stress by scavenging radicals and by metal chelation.

The authors of the study researchgate.net/publicatio... cite the following study ncbi.nlm.nih.gov/pubmed/257... “Flavone derivatives as inhibitors of insulin amyloid-like fibril formation.” Examining the data from all 265 flavones we confirmed previous observations that identified the importance of hydroxyl groups for inhibition. Our evidence suggests the importance of hydroxyl groups at locations 5, 6, 7, and 4', and the absence of a hydroxyl group at location 3, for inhibiting amyloid formation.

What makes the flavonoids Baicailein and Scutellarein such superior inhibitors of fibril formations? Baicalein includes OH-groups on positions 5,6,7 and Scutellarein includes 5, 6, 7, and 4'. Those flavonoids are some of the most potent a-syn inhibitors screened so far.

Specifically Baicailein proved in inhibiting a-syn fibrils in multiple rodent studies.

a) [Protective effect of baicalin on mouse with Parkinson's disease induced by MPTP]. ncbi.nlm.nih.gov/pubmed/181... "The preventive medication of baicalin shows a protective effect on C57 BL mouse with Parkinson's disease induced by MPTP. "

b) Therapeutic effects of baicalein on rotenone-induced Parkinson’s disease through protecting mitochondrial function and biogenesis ncbi.nlm.nih.gov/pmc/articl..."Overall, our findings indicated that baicalein exerts therapeutic effects partially through the activation of the CREB/GSK-3β/PGC-1α pathway to enhance mitobiogenesis and subsequently improve mitochondrial function."

c) Baicalein inhibits α-synuclein oligomer formation and prevents progression of α-synuclein accumulation in a rotenone mouse model of Parkinson's disease. ncbi.nlm.nih.gov/pubmed/274... "These results suggest that Baicalein could prevent the progression of α-syn accumulation in PD mouse model partly by inhibiting formation of the α-syn oligomers."

Therefore I question whether compounds with fancy name such as SynuClean-D are more potent than flavonoids such as Baicalin & Scutellarein ncbi.nlm.nih.gov/pmc/articl... It seems like the authors looked for novel lab-made compounds with a-syn inhibition properties that have not been published elsewhere, and possibly can be patented in the future for specific use.

It is very frustrating that natural and possibly safer compounds with potent a-syn inhibitory effect are often dismissed for further study and research.

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Great post Greenday, as always. My comment is that the region with the greatest presence of ultracentenarians in the world is Sardinia where the substances you mention as the flavonoids are present three times more in the diet. I wonder but will it be enough? or does stress also play its part as an inhibitor of these anti-aging reactions?

Gio

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I can also add the Island of Ikaria in your neighboring country in Greece.

1) It is the well-studied health benefits of the Traditional Mediterranean diet which includes a variety of fruits and vegetables, extra virgin olive oil, whole wheat products, sheep & goat milk, cheese and yogurt instead of cow’s, plenty of fishes and nuts, honey instead of sugar

2) The sense of the community and the family bond

3) The temperate weather

4) The clean & stress-free environment

5) the plenty of natural space and outdoor activities, such as hiking, trekking, biking and swimming.

6) the minimal use of car and public transportation.

7) sense of personal satisfaction and general well-being

8) In the case of Okinawa Island in Japan, which also tops in the list of the most centenarians, I can add the widespread use of fermented foods, rich in beneficial yeast and bacteria, and the healthy benefits of the soya beans, rich in nutrients, phosphatidylcholines and potent isoflavones such as genistein & daidzein

All these factors can delay, postpone even reverse gene mutations that lead to degenerative and other debilitating diseases.

The possible cause of PD is the oxidative stress. In both idiopathic and genetic cases of PD, oxidative stress is thought to be the common underlying mechanism that leads to cellular dysfunction and demise. ncbi.nlm.nih.gov/pmc/articl...

The surprising fact is that emerging evidence suggests that α-synuclein can propagate from cell-to-cell in a prion-like manner progressively engaging additional brain regions, and that this spreading might contribute to the symptomatic progression. ncbi.nlm.nih.gov/pmc/articl...

Quite recently a functional link between gut bacteria and neurodegenerative diseases is being unexplored. Clinical and pathological evidence show that misfolded α-synuclein is found in intestinal nerves before it appears in the brain. This suggests a model in which PD pathology originates in the gut and spreads to the central nervous system via cell-to-cell prion-like propagation, such that transfer of misfolded α-synuclein initiates misfolding of native α-synuclein in recipient cells. ncbi.nlm.nih.gov/pmc/articl...

What I can tell is that certain polyphenols in fruits, plants and veggies exhibit potent neuroprotection, anti-tumor and and anti-inflammatory effect and should be further studied, as they are abundant, safer and possibly more effective than other chemical alternatives.

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I don't know if you are aware of this very small (n=1) study titled:

"A diet low in animal fat and rich in N-hexacosanol and fisetin is effective in reducing symptoms of Parkinson's disease"

Fisetin from strawberries!

ncbi.nlm.nih.gov/pubmed/228...

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Fisetin has been tested as a weak inhibitor of a-synuclein fibril formations healthunlocked.com/api/redi... . However Fisetin may indirectly exhibit neuroprotective effect by inhibiting several apoptotic and inflammatory pathways, which play important roles in the initiation and progression of PD. ncbi.nlm.nih.gov/pubmed/239...

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This talks about berries' positive effect on signaling in the brain:

pubs.acs.org/doi/abs/10.102...

And this video mentions several similar studies:

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Is SynuClean-D a synthetic molecule?

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Thanks Greenday

Is this compound edible by humans? Like Mannitol?

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Edible only by worms. The lab that synthesize it is cited as Maybridge, Ltd.

maybridge.com . You may try contact them

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Thanks. The link is broken.

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The link is broken.

Is this correct one?

maybridge.com/portal/alias_...

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yes

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Many thanks.

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Do worms have the Blood Brain Barrier like humans?If yes was this molecule able to cross the worms BBB?

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Depends on the definition of "brain". Worms have a very primitive brain of approximately 300 neurons that connects with nerves from their skin and muscles and have no brain barrier. Nothing close to the 86 billion neurons in human brain.

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