#31

nutritional supplement | My Site (parkinsonclub.de)

#32

Heard that Mucuna Pruriens helps people with Parkinsons. I take it for mood improvement but and it really helps, but don’t know about Parkinson’s but could be worth a try.

#33

Is Mucuna pruriens any better than taking L-dopa directly? L-dopa effectiveness gradually decreases in people with Parkinson’s and they need higher and higher doses, while levodopa also comes with side effects such as bradykinesia.

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#34

Never tried L-Dopa so couldn’t say about difference…

#35

I can’t find the links now but back when I did a deep dive on metformin I came away satisfied that all its potentially negative effects on Parkinson’s and other neurodegenerative conditions could be accounted for but its property of severely impairing vit B 12 absorption and availability which has downstream consequences for neuronal myelination, cholinogenesis etc.

You can probably find the actual link somewhere in the intersection of these:

https://scholar.google.com/scholar?hl=en&as_sdt=0%2C20&q=Parkinson+vitamin+b12+deficiency+&btnG=

https://scholar.google.com/scholar?hl=en&as_sdt=0%2C20&q=metformin+vitamin+b12&btnG=

So anyone taking metformin should pair it with megadoses of Vit B12. That’s exactly how it’s bundled in one of those US based longevity focus online pharmacies. Once you take care of vit B12 depletion there doesn’t seem to be any other side effects from metformin.

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#36

……unless you’re also taking miglitol (or acarbose, if it’s a class effect) with your metformin.

I’ve posted about this before (see link below), but didn’t get any replies

For all those who use metformin and alpha-glucosidase inhibitor

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#37

Well, the little bit of Sinemet I take (100mg before my exercise class and another 100 later if I am going somewhere fancy, like a party) makes me so nauseated I can’t imagine taking mucina. It may be “natural” but it’s missing the carbidopa that keeps the dopamine from activating before it gets to the brain.

#38

Have you tried quercitin? I think it might help. Also, I take ambroxol (though I have a GBA mutation so I believe it makes particular good sense for me) and also, exenatide. I’m thinking about dasanitib, though with the quercitin plus rapamycin I wonder if it’s overkill.

Basically, I look for phase 3 trials and (since I never seem to qualify) duplicate them myself if I can. But I don’t care so much about symptoms as I do about progression.

#39

What do you consider an appropriate megadose of B12?

#40

A squirtful of this or similar: https://a.co/d/4ZxNHAE

#41

Interesting. You should look at what Cure Parkinson’s UK is doing: they only fund disease-modifying trials using repurposed drugs or supplements. Easy to replicate:

They’re now also leading an early-stage preclinical study of three compounds:

  • Benfotiamine (a form of vitamin B1),
  • Methylcobalamin (a form of vitamin B12),
  • The anti-inflammatory drug, ibuprofen.

Their trial of the anty-hypertensive drug isradipine (taken orally) failed in the past but they’re now exploring intranasal isradipine as they think it’ll increase the delivery to the brain and work this time.

Regarding GLP1 agonists, in the 2017 Phase 2 exenatide study, the stablization of the motor features was only observed in the off-medication state. I understand from the preliminary Phase 2 lixisenatide study results that the stablization of the motor features was observed in both the on and off medication states. Still, exenatide seems best at brain uptake (if I understand the graph correctly…): https://twitter.com/foltynie/status/1735700379491307973

Also, regarding exenatide, it’s possible that twice-daily is better than once weekly (unclear though, but good to have in mind that once weekly was chosen for the phase 3 because it’s easier to administrate and to ensure patients’ compliance with the treatment): Exenatide — the latest trial results explained | by Claire Bale | Parkinson’s UK | Medium

Here’s a review of other potentially interesting repurposed compounds (Nilotinib/Bosutinib and Candesartan/Telmisartan are mentioned): RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia—an international Delphi consensus | Alzheimer's Research & Therapy | Full Text

I think clinical trials for SGLT2 inhibitors on PD will also soon (~1y?) start. See this recent study on rodents for rationale: Empagliflozin repurposing in Parkinson’s disease; modulation of oxidative stress, neuroinflammation, AMPK/SIRT-1/PGC-1α, and wnt/β-catenin pathways

I’m pretty convinced that one of the aforementioned repurposed compounds will prove slow the progression in a phase 3 trial in the next few years. The exenatide phase 3 trial ends next month and we’ll get results soon hopefully.

Other interesting compounds that are under study or may be worth studying: taurine, photobiomodulation (red/infrared light similar to SYMBYX PDCare), rapamycin (although it failed for MSA), low dose CoQ10 (~150mg/d, higher doses failed), low dose lithium (there’s an ongoing trial), glycine, and astaxanthin.

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#42

Enhanced mTORC1 signaling and protein synthesis in pathologic α-synuclein cellular and animal models of Parkinson’s disease

Inhibition of mammalian target of rapamycin complex 1 mTORC1 normalized protein synthesis, decreased loss of dopaminergic neurons, and ameliorated behavioral deficits in fly and mouse models.

Great paper published last month (but I somehow missed it) about rapa for PD, by JHU researchers. See also the related press release: New Findings About Key Pathological Protein in Parkinson’s Disease Open Paths to Novel Therapies | Johns Hopkins Medicine

Treating the genetically engineered mice with rapamycin, a drug that targets mTOR, not only prevented excessive protein production in mice with a condition like Parkinson’s disease, but also eased some of the slow, halting movements and weak grip strength that are hallmarks of Parkinson’s disease in people. […] Researchers may, for example, develop drugs that act like rapamycin — currently used as an anti-rejection and anti-cancer medication — but work specifically in the brain to save dopaminergic neurons, sparing patients unnecessary body-wide side effects."

Could intranasal rapamycin do the job? Does anyone have the article to check the dose they used?

@TomParkinson: something else to try? :sweat_smile:

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#43

When I am looking for a paper that has been published recently (the ones pre-2021 are on Sci-Hub.ee) I go to twitter and try to find the author (or one of the authors) to see if they have posted a link with the code to read the full article. Many of them do this I’ve found (or I contact them on twitter to ask them to if they haven’t).

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#44

And another new paper related to these discussions (in pre-print):

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#45

“In contrast, our results showed that 20 mg/kg rapamycin administered pre- or post-MCAO decreased the volume of damage by 35–45%.”

20 mg/kg?! :flushed: Even for mice that’s a lot, no?

#46

Yes, 20mg/kg is pretty high for rodents but I’ve seen studies of up to 100mg/kg (short term obviously). Kaeberlein/Bitto did the transient rapamycin lifespan study with 3 months at 8mg/kg (injection). Seemed to go well for the male mice, but a plateau for female mice.

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#47

Found the preprint of this paper - should have the details you seek:

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#48

Thanks. “intraperitonially with rapamycin (6 mg/Kg; #R-5000, LC laboratories) or vehicle (10% PEG400, 10% Tween 80 in water) on the day of the intrastriatal α-syn PFF injection and every two days thereafter following the intrastriatal α-syn PFF injection for 30 days.”

How does rapamycin absorption differs from intraperitonially VS orally?

#49

No studies I’m aware of off the top of my head, in humans.

In mice - here is some data:

General: Why is it possible for mice to take high rapamycin doses daily?

Specific Equivalents: Concerns on improving Cmax and plasma halflife - #10 by RapAdmin

And see discussion in this paper: Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice - PMC

We initially used a treatment regimen consisting of intraperitoneal (i.p.) injections of 8 mg/kg rapamycin daily for 90 days. This dose was selected because we have previously found that it increases survival and alleviates disease phenotypes in short-lived mouse models of dilated cardiomyopathy, muscular dystrophy, and the severe mitochondrial disease Leigh Syndrome (Ramos et al., 2012; Johnson et al., 2013). Based on efficacy in the Leigh Syndrome mouse model and serum drug levels in wild type mice, we estimate that this treatment regimen is comparable to dietary delivery of eRapa at approximately 378 ppm (Johnson et al., 2015), or 27-fold higher levels than initially shown to extend lifespan in mice when continuous treatment is initiated at either 9 months or 20 months of age (Harrison et al., 2009; Miller et al., 2011)

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#50

I’ve done a bit of i.p dosing in the past. It’s a bit of a half-way route of drug administration (between oral and i.v)

Intraperitoneal injection bypasses first-pass metabolism from the gut, but is still subject to first-pass metabolism by the liver, since absorption is via visceral peritoneum which drains into the hepatic portal vein.

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