#402

Melatonin is indeed a case where reverse causality is often present as most people only take it because they have bad sleep, hence the correlation. That said I would guess that it’s totally different for people megadosing for other reasons.

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#403

As I read it, only the error bar crosses the line for melatonin. Melatonin looks to have little or no effect.

What is more interesting to me is Gingko Biloba, which is known to increase blood circulation to the brain. From the list, if I were going to pick one supplement to ward off Parkinson’s, it would be Ginko Biloba.

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#404

You can also argue that all people with Parkinson’s have sleep issues to some extent and that those who take melatonin are those who take care of their sleep the most. (Playing the devil’s advocate here.)

From what I remember clinical trials of melatonin in PD improved sleep but not other symptoms. Not a great signal.

But with melatonin the dose + timing (before sleep? After waking up?) matter a lot. So… The jury is still out.

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#405

The number of users is too small to conclude anything. But as she said in the report: after these good results for Gingko Biloba we can expect many people with PD to start supplementing with it so in the next study in a few years we’ll have more data that could confirm or infirm the result.

Also, there’s not much data supporting Gingko Biloba in the literature for PD.

From the list I’m most surprised by oral glutathione VS NAC. There’s one good trial of NAC in PD and NAC is a rate limiting precursor of glutathione. So I would expect NAC to do as good as glutathione. And yet…

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#406

I think PD is a mitochondrial problem. Hence Yang Qi herbs should help. Having a combination of Yang Qi (AMPK activators) may be a synergistically positive approach.

#407

Would there be an increased risk of heart attack/stroke with administration of exogenous PF4 in the non-surgical setting since it promotes coagulation?

#408

PD-like pathogenesis induced by intestinal exposure to microplastics: An in vivo study of animal models to a public health survey

Hua Bai et al. J Hazard Mater. 2024.

Abstract

Highlights:

  • Chronic microplastics exposure damages the intestinal barrier and accelerates PD-like phenotypes in mice.
  • Microplastics facilitate neuroinflammation by triggering excessive ROS production and sustained UPRmt.
  • MPs detection and intestinal phenotypes are associated with a high frequency of disposable plastic use.

With the increasing incidence of non-hereditary Parkinson’s disease (PD), research into the involvement of specific environmental factors, in addition to aging, has become more prominent. The effects of microplastic exposure on public health have gained increased attention as it is known to cause a range of neurotoxic changes, some of which are similar to the pathological features of PD. We carried out low-dose microplastic exposure experiments on mice and Caenorhabditis elegans models and implemented a survey regarding the utilization of plastic products in the population. We found that low-dose microplastic exposure accelerated dopamine neuron degeneration and the onset of movement disorders in vivo, inducing a PD-like neuronal pathology through its effects on the intestinal mucosal barrier, immune barrier, and microbial barrier. Notably, non-penetrating microplastics facilitated neuroinflammation by triggering excessive reactive oxygen species production and a sustained UPRmt. Furthermore, our population survey demonstrated that inappropriate use was a major source of microplastics in the gastrointestinal tract. The high use of disposable plastic tableware, especially in those with definite microplastic exposure, was also associated with intestinal inflammatory symptoms. As a novel pollutant, microplastic exposure in vivo undoubtedly executes an important role in the degeneration of dopamine neurons, regardless of barrier penetration, which is a non-independent risk factor that cannot be ignored in the pathogenesis of PD. [PMID: 39397046]

PubMed Abstract

Full Text (Paywall)

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#409

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AMPK seems hyper-activated in PD. So taking AMPK activators might not help…

Source: Neuronal AMP-activated protein kinase hyper-activation induces synaptic loss by an autophagy-mediated process 2019

:thinking:

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#410

It may be that the cells already recognise they are short of energy and hence are activating AMPK, but for some reason or other are not getting enough from the mitochondria.

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#411

Right, But many things activate AMPK, so should they be avoided? For example exercise strongly activates AMPK - yet exercise shows benefits in PD, at least in the early stages of PD. I suspect JH is right, the problem might not be with activating AMPK, but downstream from AMPK, somehow the signalling doesn’t work. The increase in AMPK, might be a compensatory attempt, since the signal is not getting through. That might explain why exercise works in early PD, because there is still some signalling downstream from AMPK, and inreasing the levels through exercise helps with the inefficiency.

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#412

Yes it’s possible. Alternative theories:

  • Exercise might also be beneficial despite AMPK activation due to other pathways that result in a net positive effect.
  • AMPK activation by exercise vs supplements or drugs might differ: location (muscles vs brain vs liver, etc.), acute vs chronic activation, etc.
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#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.