Vlasko
#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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adssx
#409
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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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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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adssx
#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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adssx
#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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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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adssx
#415
Everolimus crosses the BBB. Sirolimus does not. Another paper found a similar result: Parkinson's disease - #154 by adssx
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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.
adssx
#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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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?
adssx
#420
I checked N-acetyl-leucine (tanganil). My concerns:
- 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).
- The L form might be more potent (and maybe safer) and that’s probably why IntraBio chose it for this rare disease.
- The DL form (tanganil) has been tried in MSA-C (a condition close to PD) and failed.
- 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).
- 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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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.
adssx
#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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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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adssx
#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).
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(
adssx
#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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adssx
#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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