Complex 1 inhibitors cause aggregation of... - Cure Parkinson's

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Complex 1 inhibitors cause aggregation of a/syn and tau.

MBAnderson profile image
20 Replies

Getting rid of inhibitors gets rid of aggregates (What Nilotinib is supposed to do).

A lot of (ordinary) things are inhibitors and they are adding to the list all the time:

Examples:

Aspirin

Tetracycline, doxycycline, etc.

Oxylates (spinach)

Alcohol

Beta blockers

Some antidepressants

Metformin

“Here we provide evidence that the functional state of mitochondria might be a key determinant for aggregation of α-syn.

In addition, the aggregates appeared to be eliminated by restoring normal mitochondrial metabolism, suggesting the presence of cellular mechanisms that actively disassemble and degrade protein aggregates.”

m.jbc.org/content/277/7/541...

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MBAnderson
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Xenos profile image
Xenos

Very interesting paper. What surprises me is that it was issued in 2002.

sharoncrayn profile image
sharoncrayn

11/04/2020---

MBA,

"Getting rid of inhibitors gets rid of aggregates (What Nilotinib is supposed to do). "

Try to watch your analysis of some of these studies you reference and your wording. Often you are completely wrong or misleading with your wording unintentionally.

PwP want to do Just the opposite of what you wrote. A-syn aggregation inhibitors like mannitol inhibit (prevent) the negative aspects (so-called inclusions and misfolding) of a-syn aggregation, which presumably are a major factor in causing PD and probably other neurodegenerative diseases.

Therefore, PwP want to avoid the progressive accumulation of the presynaptic protein α-synuclein (α-syn). Inhibitors can't accomplish this completely, but they help mitigate (slow) the process.

Your list of meds/supplements isn't exactly accurate. LPDMs do work in cell studies (spinach). Aspirin? Alcohol?

Sharon

MBAnderson profile image
MBAnderson in reply tosharoncrayn

Sharon,

To be honest with you, I don't see a relationship between my comment and the link I posted. And, I appreciate being corrected, which is a regular occurrence (and a good way to learn,) but you point out that a/syn aggregation inhibitors inhibit a/syn aggregation while I was referring to complex I inhibitors which I think impairs mitochondria performance which increase a/syn aggregation.

Be that as it may, since I posted that comment a year ago I have gotten away from basic science in petri dishes, such as complex 1, because nowadays my eyes glaze over reading this stuff, i.e., it is well over my paygrade, I question its relevance and have since tried to only post stuff that we can actually do and that's immediately helpful.

Is the world a better place if I delete the thread?

marc

sharoncrayn profile image
sharoncrayn in reply toMBAnderson

MBA

The paper you cited has a very good explanation of the importance of mitochondria. Excellent. But the issue isn't simple.

You said: "I don't see a relationship between my comment (not sure what comment - sharon) and the link I posted." It should exist.

You said: "complex I inhibitors which I think impairs mitochondria performance which increase a/syn aggregation." The authors concur with your statement.

Authors write: "These results suggest that the formation of α-synuclein inclusions could be initiated by an impaired mitochondrial function and be reversed by restoring normal mitochondrial metabolism. " We could also say...From anything that might impair their function which covers a lot of things.

Authors write: "mitochondria from PD patients showed reduced complex I activity ... administration of rotenone, an inhibitor of mitochondrial complex I, recapitulated (recreated - sharon) the major pathological and behavioral features of PD" YES. but look below at the implication for PD with groups such as farmers!

You said: "Getting rid of inhibitors gets rid of aggregates (What Nilotinib is supposed to do). " Too vague and possibly misleading. It all depends on what inhibitors you are talking about!

BUT WAIT A MINUTE

Inhibitors of the mitochondrial respiratory chain complex I are suggested to exert anti-tumor activity on those tumors relying on oxidative metabolism and are therefore of interest to oncology research. IOW, in the cancer world, Complex 1 inhibitors have shown anti-carcinogenic activity in several studies...

BUT WE FOCUS ON PD

Therefore, If you only knew what rotenone was you could have gone several steps further like the authors implied but didn't.

Rotenone = common pesticide = example of Complex 1 inhibitor = creates mitochondrial dysfunction = causative variable in causing PD. And squamocin and otivarin, also behave qualitatively like rotenone, both in terms of PD, but also cancer.

Black is not always black unless you blind yourself to the possibility of white.

Keep the thread up. It is relevant.

Sharon 11/05/2020

Rhyothemis profile image
Rhyothemis

There's reason to think that metformin may actually be beneficial:

sciencedirect.com/science/a...

frontiersin.org/articles/10...

There are some conflicting findings from epidemiological studies on metformin use and risk of developing PD, however.

MBAnderson profile image
MBAnderson in reply toRhyothemis

I agree. A lot of people to think Metformin is also an antiaging drug. I don't think it's so hard to control our blood sugar through diet, fasting and exercise, though.

sharoncrayn profile image
sharoncrayn in reply toMBAnderson

MBA,

"There's reason to think that metformin may actually be beneficial"..."I agree (MBA)..."

Be careful with this drug, very careful. Metformin inhibits mitochondrial complex I ...so it has a definite down side for PwP.

Therefore, are you sure you want to go there with your very, very serious PD? Is this drug Beneficial to halting your PD progression with what we know? Just the opposite.

This is exactly why this thread should stay up. This is why you have to be very careful with what you say on your Zoom call in show. You can unintentionally do more harm than good without realizing it.

Sharon

11/06/2020

JayPwP profile image
JayPwP in reply tosharoncrayn

Sharon, is the date wrong? :)

1/06/2020

sharoncrayn profile image
sharoncrayn in reply toJayPwP

no.... 11/06/2020

MBAnderson profile image
MBAnderson in reply tosharoncrayn

Ms. Crayon,

I titled the thread, "Complex 1 inhibitors cause aggregation of a/syn and tau." and then went on to say, "Getting rid of inhibitors gets rid of aggregates..." While it could be considered vague, if that's how a person chooses to read it, it could just as easily be seen as what I intended, i.e., referencing complex 1 inhibition.

As far as I can tell you agree that rendering complex 1 dysfunctional impairs or renders mitochondria dysfunctional which increases a/syn aggregation, yet you go on to say I am completely wrong or misleading and say that PWP should do just the opposite citing as an example mannitol being in inhibitor of a/syn aggregation when, again, considering the title of the thread, (most would know) I was referring to complex 1 inhibition.

So rather than asking for clarification, you choose an interpretation that is incorrect and then argue against it.

Regarding Metformin, the only thing I said about it was I listed it as a complex 1 inhibitor which you agree with.

Rhyothemis then commented,

"There's reason to think that metformin may actually be beneficial . . . There are some conflicting findings from epidemiological studies on metformin use and risk of developing PD, however." to which I said, "I agree."

You then admonished me, essentially, as though I made the case that metformin is good for us which I did not do. When I said "I agree," I was agreeing that it may be beneficial and that there are conflicting opinions.

Metformin may be beneficial. You do not get to choose what the word "may" means. There are thousands of doctors and millions of people who believe it is.

A fair-minded reader would have noted that I went on to say I choose (not to take metformin but) to control my blood sugar via dieting, fasting, and exercise.

I get things wrong and when I do I'm happy to admit it, but the concern I have with your critiques is that you're cherry picking interpretation. I believe a fair reading of my words would interpret them the way I intended them.

"If you only knew what rotenone was..." That's an assumption without any basis.

marc

sharoncrayn profile image
sharoncrayn in reply toMBAnderson

I have to strip and clean my Beretta before going in to work on Monday. You know how these peaceful protests are. Would love to continue to quibble over semantics, but I have to move on.

We both agree Complex 1 inhibitors are destructive to your brain's mitochondria.

"A lot of (ordinary) things are inhibitors"... still talking about Complex 1 inhibitors? Really? LOL.

Sharon

Rhyothemis profile image
Rhyothemis in reply toMBAnderson

I don't think the effects are entirely due to improvement in blood sugar control per se and may be attributable to AMPK activation. Exercise also activates AMPK, though, without side effects or risks of metformin.

Rhyothemis profile image
Rhyothemis in reply toMBAnderson

Some news on metformin - a study of C. elegans (worms) and human cell cultures found that older individuals had deleterious effects while younger individuals benefited. Co-administering rapamycin alleviated the toxic effects in older individuals:

medicalxpress.com/news/2020...

I am curious to know if boosting NAD would also mitigate the toxicity.

Coincidentally I also saw yesterday a video presentation on the effects of aging on microRNA production in response to exercise. An enzyme called Dicer is involved in RNA processing and it increased in activity in response to exercise; the effect size was found to be much lower in older individuals and the effect is AMPK dependent.

youtu.be/lN_wJT-EkuA

sharoncrayn profile image
sharoncrayn in reply toRhyothemis

Metformin inhibits mitochondrial complex I ....

Sharon

Rhyothemis profile image
Rhyothemis in reply tosharoncrayn

Metformin's complex I inhibitory activity is reviewed in the second article I cited (first one is paywalled so it doesn't really count I suppose).

There's also this:

Metformin Linked to Better Motor Function in Parkinson's

medscape.com/viewarticle/93...

Of course, a clinical trial is needed.

A trial of low dose rapamycin and metformin for MSA or PD would be interesting.

chartist profile image
chartist

Marc,

Melatonin may be another solution to the problem, at least in a rat model.

pubmed.ncbi.nlm.nih.gov/234...

Melatonin is a very interesting molecule! Oh wait, I already said that before! 😀

Art

sharoncrayn profile image
sharoncrayn in reply tochartist

Chart,

An essential supplement.

"melatonin is neuroprotective against mutant alpha-synuclein-induced injury in the substantia nigra. " ( Hampsters jump for joy!) Actually melatonin and its metabolites do impact the brain's mitochondria in a positive manner due to its amphiphilic nature.

"Melatonin is (cap)able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival."

Sharon

chartist profile image
chartist

Sharon,

Yes, melatonin seems quite adept at dealing with many PD associated issues as well as other disease states, unfortunately melatonin levels decline as we age and by the time we reach 50 years of age, production is back down to the level of a 1 year old baby. By age 65, melatonin levels are very low. Declining melatonin levels when we need it most is not a good thing in terms of diseases that are age related such as PD and AD, but melatonin supplementation has already shown benefit in both diseases at low dosage such as 10 mg/day.

What is lacking is high dose human studies of melatonin in PD and AD. This 2020 study in T2DM patients using 250 mg / day of melatonin for 8 weeks clearly shows that melatonin starts to return oxidative stress levels and inflammatory mediators toward homeostasis in just 8 weeks.

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

In other HDM studies of longer duration melatonin does return redox status and inflammatory mediators to equilibrium or to levels of healthy controls and that would be a very good thing for PD and AD among many other diseases. Melatonin has shown the ability to be produced in the mitochondria in order to protect against oxidative stress, but when native production in the mitochondria is insufficient, the mitochondria can draw melatonin from outside of the cell, if it is available, to improve protection status via increased TAC. Melatonin is also protective of dopaminergic neurons in the substantia nigra and can protect them against oxidative stress, inflammation and death.

In general, human studies show that melatonin dose and time dependently improves oxidative stress and inflammatory mediators to levels of healthy controls. Add in the, anticovid-19 effects, anticarcinogenic activities of HDM and its very good safety profile and this would be a blockbuster drug if pharmaceutical companies could patent it.

Art

sharoncrayn profile image
sharoncrayn in reply tochartist

"clearly shows that melatonin starts to return oxidative stress levels and inflammatory mediators toward homeostasis in just 8 weeks. " I didn't get that impression. You understand they focused primarily on serum levels for MDA.

"What is lacking is high dose human studies of melatonin in PD and AD. This 2020 study in T2DM patients using 250 mg / day of melatonin for 8 weeks "

The Periodontal/T2DM human CT using 250 was pretty extreme (see their "discussion" which clearly shows it was.)

I would say that the LUND MICE/cell biology gene variant study and the later human trial using 4 mgs./day was a moderate dose. Even though the LUND dose was moderate, it increased "signalling" power or throughput which is also an issue for PwP when it comes to L-Dopa and dopaminergic neurons.

The problem for PwP types is that the link between diabetes and PD is weak to non-existent but relatively strong between Type 2 and low melatonin levels.

"this would be a blockbuster drug if pharmaceutical companies could patent it." You can buy melatonin at any US drugstore for pennies. Forget the conspiracy theory.

"Add in the, anticovid-19 effects" I assume you are talking about obese diabetics with diabetic cardiomyopathy.

Sharon

chartist profile image
chartist in reply tosharoncrayn

Yes on the "MDA" as other studies go into more specific detail on markers of oxidative stress which is more useful in determining all that is taking place as opposed to a general marker such as MDA. Other human studies have shown that it takes 6 months to a year of HDM to reach redox equilibrium and healthy control levels of inflammatory markers, so at 8 weeks they were only showing a trend.

Yes, on the 250 mg/day dose. I was actually surprised at that extreme of a daily dose for T2DM. That high of a dose is usually considered for cancer and ALS which can have very rapid progression . Based on other human studies, 100 mg /day seems more appropriate and has shown a very good safety profile in humans over years of daily use and has shown the ability to regain redox equilibrium and reduce inflammatory markers to healthy control levels. The 10 mg melatonin / PwP study earlier this year showed clear and significant benefit, but was relatively short at 12 weeks.

pubmed.ncbi.nlm.nih.gov/324...

My thinking is that even low dose melatonin shows measurable benefit in humans and increasing dosing suggests increased benefit, but higher dose studies for PD are lacking again leaving me to have to experiment with melatonin at 104 mg / night on my own based on its safety profile, as that study may or may not ever occur.

Sharon, there is no "conspiracy theory" in my discussion and I don't know where you got that from. That is simply good business. You invest where you can maximize the return on your investment so human studies for HDM are most likely to be far and few between and that is another reason I was surprised to see the 250 mg study, ever. That's just keeping it real.

I did not mention a link between PD and T2DM. I merely selected that study because of the dose used. Melatonin levels are generally lower in PD and AD, but not always.

As far as I am aware, none of the melatonin/Covid-19 human studies have completed yet, though the Manila study should be close to completion. That comment was based mainly on Dr. Neels experience in his Covid-19 patients and the initial trial from Manila and one other recent study. When that trial completes and they release their data, I will add it to the Covid-19/melatonin thread.

Art

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