#413

Exploring the Neuroprotective Potential of Immunosuppressants in Parkinson’s Disease 2025

Medicare beneficiaries using the calcineurin inhibitor tacrolimus (RR 0.49, CI 0.40-0.60) and mTOR inhibitors everolimus (RR 0.38, CI 0.26-0.56) and sirolimus (RR 0.59, CI 0.37-0.93) had a lower risk of PD compared to those not taking the medication. The TNF inhibitor certolizumab was also associated with lower PD risk (RR 0.54, CI 0.34-0.84). Tacrolimus and everolimus remained significant after Bonferroni correction. Sensitivity analyses otherwise confirmed results for all four medications.

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Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?
#414

Interesting that everolimus has an even better hazard ratio than rapamycin. Is everolimus a better longevity drug? Why might that be?

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#415

Everolimus crosses the BBB. Sirolimus does not. Another paper found a similar result: Parkinson's disease - #154 by adssx

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#416

Ah, that’s right. Are there any other reasons to prefer everolimus vs rapamycin? Why do folks here tend to use the latter? Seems like getting it into the brain would be beneficial.

#417

I think there’s no data for everolimus so the case for sirolimus is way stronger. A few people use everolimus though. Use the search and you can find threads about that.

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#418

Here are a few threads:

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#419

Hey…I’d like to dredge up the N-acetyl-leucine thing again. Two articles, one here: A bit of ADLL for RBD – The Science of Parkinson's and another here: https://www.nejm.org/doi/full/10.1056/NEJMoa2310151 (and more probably).

This sounds interesting enough to me that I just bought some. Among other things, the fact that it was just approved and is suddenly a prescription drug selling for something like $13000 a month made me want to get it while I still could.

And, oh yes, it is one of the few things that seems to make a difference that can actually be seen on a brain scan (in REM sleep disorder, but that is often early stage PD).

Anyone else intrigued by this?

#420

I checked N-acetyl-leucine (tanganil). My concerns:

  1. The cognitive decline in the trial of 2 people (although it might not be that bad as noted by Simon in the blog post you linked).
  2. The L form might be more potent (and maybe safer) and that’s probably why IntraBio chose it for this rare disease.
  3. The DL form (tanganil) has been tried in MSA-C (a condition close to PD) and failed.
  4. In Small Molecule, Big Hope-Can Acetyl-DL-Leucine Reverse Parkinson’s Disease? 2024, the authors note that in PPMI, those who had RBD at baseline but later reversed it “showed the fastest motor progression” and “the most severe gray matter atrophy in the middle frontal gyrus” (Evolution patterns of probable REM sleep behavior disorder predicts Parkinson’s disease progression 2022). So reversing RBD might only be symptomatic without impacting the course of the disease (or even making it worse!). And then they note that leucine might interact with DAT binding (Molecular dynamics of leucine and dopamine transporter proteins in a model cell membrane lipid bilayer 2010).
  5. Tanganil is one of the most prescribed drugs in France. Since 1957. So surely if it prevents, cures or slows down PD we should see it in the data. I know 2 researchers looking at this. Hopefully we’ll soon get the answer. (“Soon” meaning in a few years in the world of academia…)
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#421

Do you have the source for the MSA results? Would love to read.

The funny thing about the racemic form causing cognitive problems is, you’d think if an OTC drug like Tanganil messed w/cognition you’d hear about that, too. Anyway, I’m more interested in the L form. That’s what I bought. Now I need to decide whether to take!

Just FYI, my PD is caused by a single GBA mutation. Homozygous GBA codes for Gaucher’s, another lysosomal storage disorder. It always makes me sit up and look when a drug affects any LSD…like Niemann-Pick.

#422

I posted it in the comments of the blog (sorry I’m on my phone).

Where did you buy the L form?

Yes I agree that if tanganil caused dementia it might have been caught. Even more so as it’s mostly used by people 60+ in France. However most French users use a rather low dose of one pill daily for a few weeks and then nothing, way less than in the RBD trial (check my comment on the blog post for the detailed numbers).

If you have GBA then Ambroxol theoretically makes the most sense for you. Have you tried it?

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#423

Yes, actually, I’ve been taking ambroxol since 2021. I bought the powder from India and have been making my own capsules, because the dose for PD (like Tanganil for vertigo vs N-Acetyl-L-Leucine for whatever) is MUCH higher than what you can buy OTC.

I pretty much will try anything that sounds promising, especially if there is a mechanism attached that makes any kind of sense.

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#424

I agree that makes sense.

Where do you buy your acetyl-l-leucine from? I bought some tanganil but I’d love to find a serious source of the L form (I don’t trust Chinese suppliers that much, chemical suppliers can be better but they don’t sell to retail, and I don’t live in the US so can’t buy the FDA approved one that easily).

#425

Heh–I found it on amazon (brand: Aksunder) of all places, and of course when it arrived it OBVIOUSLY came from China. So I’m a little worried.

It’s a 1000g bag of very sour, quite insoluble (in water) powder that makes me suspicious, though when we asked they told us it would be sour and insoluble. It only cost $135, and I say only because the prescription price for the exact same thing is $13,000.00 per month! So no, I pretty much don’t have access to the FDA approved one either!

There is another source and brand I found: N-Acetyl-L-Leucine, Ac-Leu-OH: AJI92 Standard & Derivative Benefits I’m tempted to buy it, just to compare taste and solubility. It’s basically $50 for 500g. If you can access that one, tell me. We can compare!

I’m also a little concerned eventually someone is going to put the cabosh on our ability to get it…I doubt the drug companies here want cheap versions of their drugs floating around. :o(

#426

Yes, I saw the Mark Nature one, but I’m not convinced of its quality either.

I think these chemical suppliers are considered reputable and serious:

Other chemical suppliers might not be as good but are 10x cheaper:

“Good” suppliers offer third-party certificates of analysis and quality. You could ask that to Aksunder. You might also pay ~$200 for a company to analyze your products.

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#427

Hypoxia therapy seems interesting in PD. We have a long discussion about hypoxia and longevity here, with some posts relevant to PD:

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#428

What is N-Acetyl-L-Leucine’s mode of action?

#429

Also, a life update on my side: I’ve just been diagnosed with Parkinson’s disease (yes, at 32yo it sucks :smiley: ). I diagnosed myself 3 years ago, so that diagnosis was an “official” confirmation. It took a long time to convince doctors, but that’s the usual journey for people with complex diseases… (Thanks a lot to @DrFraser and @dradambat for their help and support in this journey!). At least I was able to learn about the disease and start lifestyle + pharmaceutical interventions to improve my condition.

I’m looking for this Holy Grail of interventions:

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The level of evidence is often weak, and one has to make some bets on risk/benefits.

So besides lifestyle interventions (most of what Dr Laurie K Mischley recommends: MIND diet, exercise, yoga, meditation, stress management, sleep hygiene, avoiding pesticides, eating organic, a bit of black coffee and green tea, etc. + getting vaccinated for pretty much everything), I’m taking the following Rx drugs and supplements:

Intervention Biomarker(s) Neuroprotection Safety
Dapagliflozin 10 mg eGFR, HbA1C, HOMA-IR, time in range with CGM Potentially for AD & PD (association studies & animal models) Safe + might extend lifespan in rodents
Telmisartan 80 mg SBP Potentially for AD & PD (ongoing RCTs) Safe
Amlodipine 5 mg SBP Potentially for AD & PD (other DHP CCBs might be more potent though) Safe, DHP CCBs extend lifespan in worms
Ezetimibe 10 mg apoB Very weak evidence for AD & PD Safe and probably safer than statins for PD
Selegiline 1.25 mg None (mood + PD symptoms) Might be neuroprotective in PD (controversial) Safe at low dose but many drug interactions, might extend lifespan in rodents (ITP in progress)
Lithium orotate 1 mg None (mood) Ongoing trials in AD & PD Very safe at low dose, extends lifespan in worms
Methylcobalamin (1 mg/week) Serum B12 Might be neuroprotective in AD & PD Safe if serum B12 kept in normal range
Theracurmin 30 mg None Weak evidence for neuroprotection in PD Looks safe, curcumin didn’t extend lifespan in the ITP but Protandim that contains curcumin did

Dapagliflozin, telmisartan, lithium, and selegiline are the interventions where I “saw”/“felt” a direct and significant positive effect. Others (amlodipine, ezetimibe, B12, and Theracurmin) are more like “safe bets,” but I’m not sure I saw improvements (maybe for B12 and Theracurmin, but hard to tell). I’m considering switching from amlodipine to isradipine (new RCT might start soon) or nilvadipine (Australian RCT results due this year) and maybe ezetimibe to obicetrapib if it gets approved.

I’m also interested in:

  • Probiotics: I saw positive effects with Symprove, but it might only be symptomatic. It was trialed in PD at King’s College London and the first results are encouraging. Waiting for the full results to be published.
  • GLP-1RAs: exenatide phase 3 failed. I tried oral semaglutide and saw some tiny cognitive & motor improvements but offset by some mood deterioration and excessive sympathetic activation. There are ongoing trials of oral semaglutide in AD & PD: I’ll wait for the results. Or I might try microdosing tirzepatide.
  • Terazosin: pre-clinical data is very good, RCT about to start in the UK. I tried 1 mg a few times: great sleep and energy the day after. But it gave me mild orthostatic hypotension and tachycardia. It might be worth trying one month to see if the body adapts and the effects disappear. Or try 0.5 mg? Or wait for the RCT results…
  • Coenzyme Q10: RCTs at high doses failed in PD. But 60 mg/day ubiquinone is probably very safe and might be a good bet.
  • Acetyl-leucine: as discussed above. I’ll probably wait a bit before doing a test.
  • K2 MK-7 (menaquinone-7): one interesting paper + ongoing German RCT. It gives me mild insomnia, though (which is evidence of its potency on mitochondrial function per @John_Hemming )
  • TUDCA (taurursodiol): ongoing RCT of UDCA. TUDCA is probably more potent (and more easily accessible). I tried 500 mg and didn’t see any positive effects so I stopped. I’ll wait…
  • High-dose NR (Nicotinamide riboside): I think there are potential risks. RCT results due this year. I’ll wait.
  • Urolithin A: potentially more potent and safer than NR. I didn’t see positive effects when trying it though. I might give it another try.
  • Ambroxol: I took it at a low dose (60–80 mg) for 9 months and saw great improvements but then I think it gave me some benign arrhythmias so I stopped. This article (Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: A case report and literature review 2024) suggests: “As in previous reports, our patient was treated with ERT and ambroxol, and her improvement in blood data and neurological symptoms could be attributed to the combination of these agents. On the other hand, the clinical course of our patient suggests that ambroxol does not necessarily improve brainstem dysfunction leading to laryngospasm and dysphagia. Based on these findings, we speculate that the brainstem might be more vulnerable to lysosomal dysfunctions than neurons in the cerebral cortex. Thus, respiratory failure, cardiac arrhythmia and other signs of dysautonomia must be observed carefully during the follow-up period.” Ambroxol also recently failed in the PDD trial in Canada: not good. I happily take it whenever I have some cough, though :slight_smile:
  • Ibuprofen: interesting data but long-term use doesn’t seem safe. I happily take it whenever I have a viral infection, though :slight_smile:
  • Everolimus: rapamycin/sirolimus doesn’t seem to cross the BBB and to help in PD. But everolimus might. But I’m not convinced by the safety profile…

I’m also very interested in intermittent hypoxia and I’ll probably do 3 sessions next week (protocol TBD…).

If anyone has recommendations or ideas of things to try let me know :slight_smile: Prediction markets see a first disease-modifying treatment approved around 2030 (see here and there and also there) so it’s all about staying alive and in good shape until then + hope for AGI to come earlier and accelerate that timeline :sweat_smile:

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Challenge my drug stack, be ruthless but honest
Lewy Body / Parkinsons
Lewy Body / Parkinsons
#430

Whether it’s the DL form (approved for vertigo in France) or the L form (approved for Niemann–Pick disease type C in the US), I don’t think anyone knows the mechanism of action!

One assumption is that it improves lysosomal function: A bit of ADLL for RBD – The Science of Parkinson's

It might also balance the brain’s pH, get rid of lactate, and make the brain less acidic. And it might inhibit mTORC1 and improve brain glucose usage: Drug Repurposing Update #2 – Tanganil ® (Acetyl-Leucine) – Potential Mechanisms of Drug Action  – Syngap Research Fund

This paper suggests it might rebalance the gut: https://www.sciencedirect.com/science/article/pii/S0361923023001545

So… no one knows!

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#431

I think reducing acidity generally is useful. Randox do pH measurements of urine.

#432

So sorry to hear about your diagnosis at such a young age. You are a brilliant young man and you are taking positive steps to slow or halt the progression of the disease. I wish you the best in your battle. If anyone can find a way to halt or overcome it, I believe that you can!

You have my heartfelt best wishes.

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