peroxynitrite more involved than realized ?

sb4

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@debored13 Yeah, it's hard to judge, I would guess if peroxynitrite is a problem then maybe it's best to avoid but testing for that is hard. Best to just keep a journal and see if you get better or worse on those. Problem is, these effects can be subtle and build over time.

Yeah progesterone, pregnenolone, and dhea are things I want to play around with more. Problem is, my libido dropped and my balls started to hurt randomly (luckily I didn't grow breasts either). I did feel my POTS improved a little though. I tried a generic brand and Haidut's brand both at very low dosage.

I don't know what volumetric dosing is but it sounds like a smart thing to do. These things are powerful substances.
 
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@debored13 Yeah, it's hard to judge, I would guess if peroxynitrite is a problem then maybe it's best to avoid but testing for that is hard. Best to just keep a journal and see if you get better or worse on those. Problem is, these effects can be subtle and build over time.

Yeah progesterone, pregnenolone, and dhea are things I want to play around with more. Problem is, my libido dropped and my balls started to hurt randomly (luckily I didn't grow breasts either). I did feel my POTS improved a little though. I tried a generic brand and Haidut's brand both at very low dosage.

I don't know what volumetric dosing is but it sounds like a smart thing to do. These things are powerful substances.
volumetric dosing is just for when it has to be in a dose range that a scale isn't accurate enough with. then u dissolve it in a proportionate amount of a solvent so that u have the proper dose. it's simple division as far as the math goes but sometimes I can't even manage stuff like that. with DHEA the dose range is apparently particularly important, needs to be under 15 mg?, which is gonna be tough without an industrial grade microgram sensitive scale

never noticed particularly awful stuff from progestE. it did kill what was left of my sex drive, which i took to be a temporary thing that would reverse with DHEA or other androgen promoting substance, but also what do I need a sex drive for when i'm bedridden lol. so whatever. surprised that i got such bad results from pregnenolone but fairly good/benign ones from progesterone
 

sb4

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needs to be under 15 mg?
Yeah, I first dosed at around 5mg of DHEA and Preg each. Then I used haiduts version at 1 drop = 1.25mg of each. Then I diluted it with 99% Alcohol to 0.125mg each. Still had bad reaction at this dose (sleep was worse).

but also what do I need a sex drive for when i'm bedridden lol
Yeah I know what you mean but the ball pain was err ... worrying :(.

surprised that i got such bad results from pregnenolone but fairly good/benign ones from progesterone
Yeah, I want to try progesterone at low dose sometime. I tried it at relatively moderate dose in morning once, didn't notice anything until night time where I had terrible insomnia.
 

vortex

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Ahh, my old thread seems to have been resurrected!

For those wondering if you do indeed have excess peroxynitrite you can have your nitrotyrosine levels tested to see if they are elevated.

This will give you a good indication if you have excess peroxynitrite.

I spoke with an online testing company to offer HDRI items to their list of lab tests available
to order online without a doctor.

https://www.truehealthlabs.com/Nitrotyrosine-p/health_dx_nitrotyrosine.htm

If you already have a doctor that will order this test for you, then great but
many dont have a doctor or it would cost much more for visits and followups
with the doctor rather than just ordering direct.

I think I posted it in the first post but my research shows that gamma fraction of vitamin E
scavenges it, so that would be gamma tocopherol and an even more powerful scavenger
would be gamma tocotrienol.
Also astaxanthin can scavenge it, but not sure which one is more effective.
 

Learner1

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Sorry, just noticed this now. I have done the HDRI test for NO and nitrotyrosine @vortex mentions, which dhowed that I had high levels of both - nitrotyrosine is a marker for peroxynitrites.
The post basically showed that when you stop ONOO from forming, you stop peripheral neuropathy, and when you increase ONOO you increase neuropathy. It seems to work by the ONOO reacting with the tyrosine side chains of the microtubules. It does this easier on nerves that are poorly myeliated (SFN?).
I know that peroxynitrites will damage membranes and they will inhibit complex I of mitochondria, so it would makes sense they could cause SFN. This article seems to suggest so, too:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177961/

Peroxynitrite has multiple cytotoxic effects that include

1) protein nitration and nitrosylation;

2) DNA single-strand breakage and base modification;

3) activation of poly(ADP-ribose) polymerase with resultant changes in transcriptional regulation and gene expression;

4) changes in cell signaling;

5) mitochondrial dysfunction; and

6) necrosis and apoptosis [26–28].

Accumulation of nitrotyrosine, a product of peroxynitrite-induced protein nitration, has been documented in peripheral nerve [31], vasa nervorum [7–9], and dorsal root ganglion [32] in streptozotocin-diabetic rats, and peripheral nerve, spinal cord, and dorsal root ganglion of streptozotocin-diabetic and ob/ob mice [31,33–35] indicating that diabetes creates not just oxidative, but oxidative-nitrosative stress in the peripheral nervous system
Oxidative and nitrosative stress and pero nitrite formstion to have been written abput in ME/CFS - see attached.

The post goes on to say that progesterone, pregnenolone, and gama-tocopherol should have a protective effect via stabilizing and myelinating the tubules, and binding with ONOO. This is interesting as I noticed improvement in some POTS symptoms when using DHEA and Pregnenolone, however it had some bad effects on libido and other issues causing me to stop.

It also says how things like methylene blue can cause worsening neuropathy by increasing ONOO (MB increases super oxide formation causing more NO to turn into ONOO). Interestingly enough I was on MB when a drastic worsening of my POTS occurred.
Mehylene blue seems to be an antioxidant that can inhibit superoxide production in this experimental use:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177961/

I'm not familiar with it, but in general, there are 2 sides to antioxidants - they can also become pro-oxidants once used and need to be recycled back. I dont know what recucles methylene blue.

What do you think @Learner1 ?
I'm working with an excellent naturopathic/functional medicine doctor, and methylene blue has not neen mentioned. Rather, we are following Pall's advice by keeping my methylating nutrients high and supplementing viramin C and glutathione. Glutathione can neutralize peroxynitrites.

I suggested working on the BH4, but my doctor says he and Ben Lynch have tried it in the past without much effect, snd it's been patented as a rare disease drug, Kuvan, in 2 dozen countries and is extremely expensive.

I have had good results with kerping glutathione high - not overdoung it, as that could backfire, but it reduced/reverses PEM and I am functioning better since adding it.

We are also assuming a great deal of membrane damage and I've been using Garth Nicoldon's lipid replenishment strategy by taking 2-3 scoops of NT Factor daily and getting a phosphatidyl choline IV every 2 weeks, which I've noticed an immediate bump from.

As for hormones, I'd recommend a DUTCH test and adjusting based on the results. Dried Urine Test of Comprehensive Hormones.
 

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I would like to put for the theory that peroxynitrite is a significant obstacle to
healing via methylation protocol in ways we havent realized by interfering
and or destroying much of our effort by the methylation protocol and some
degree of success in the methylation protocol comes from an inadvertent
co-treating and overcoming peroxynitrite.

In other words, peroxynitrite is contributing to keeping the mitochondria
shut down in more ways than is attributed in the current theory.

richvank theory mentions peroxynitrite inhibits methylfolate in #3 but leaves
out some important details of its real impact in other areas downstream.

http://forums.phoenixrising.me/inde...tion-cycle-block-hypothesis-for-me-cfs.15701/

Yes, peroxynitrite inhibits methylfolate but it also has its hand in shutting down other cycles
in the methylation cycle and glutathione cycle.

Peroxynitrite directly induces destruction of the tetrahydrobiopterin
http://www.ncbi.nlm.nih.gov/pubmed/20184376

Peroxynitrite Inactivation of Glutathione Peroxidase
http://www.sciencedirect.com/science/article/pii/S0003986197904070

But in #4 Rich attributes "Glutathione depletion lowers the affinity of the CblC"
as the start of the block/cause, theorizing this is shutting down "methionine synthase reaction" causing the block and focusing on this can fix things.

Although he then goes back to and mentions peroxynitrite in #7
"The elevated peroxynitrite catabolizes methylfolate, preventing its rise in the plasma"
he mentions it inhibits methylfolate which could contribute to some of this block but
then stops there and goes back to b-12. It almost seems like the peroxynitrite is incorporated
into this theory by mentioning it and saying its impact is that it inhibits methylfolate but then
stops short there.

He then goes back to b12 in #13 by saying the treatment should revolve
around the b-12

"dosage of B12 is necessary to compensate for the greatly lowered affinity for cobalamin of the CblC complementation group, so as to overcome the functional B12 deficiency,"


So if peroxynitrite can inhibit glutathione recycling and destruction of BH4 in addition to destruction of methylfolate which inhibits methionine synthase, who knows, this might be the real reason glutathione doesnt come back up and causes CFS instead of b-12. I think peroxynitrite is interfering with more steps than we realize and that by treating this with methylation boosters like methylfolate and methylcobalamin we arent just restoring methionine synthase reactions, but we may be treating peroxynitrite directly with the supplements we are using or indirectly by overdriving methionine synthase to compensate for peroxynitrite effects of destroying bh4 and glutathione peroxidase.

hydroxocobalamin is a peroxnitrite scavenger, which may explain why people are having a good response to this cobal over methylcobalamin which should be the only one that significantly boosts methionine synthase.

Also methylfolate is a peroxnitrite scavenger, so it makes you wonder how much methylfolate is going towards quenching peroxynitrite and how much is going towards methionine synthase ?

So it seems like peroxynitrite is destroying alot of our efforts and is like stepping harder on the gas while having the brakes on or turning the faucet on faster to try to fill the sink because the drain is partially open.

So I think that if this is true, then we should focus more on directly addressing peroxynitrite/nitrotyrosine scavenging directly so we dont have to put all the load on the methionine synthase reaction to overcome all of the destruction that peroxynitrite is causing.


So perhaps adding more peroxynitrite scavengers to the methylation protocol can help non-responders and or alter or reduce some of the doses of the methylation boosters so we dont have to compensate so much for all the destruction that peroxynitrite is doing to our efforts.

gamma tocopherol is a known peroxynitrite scavenger, can someone add to this list ?

This document by pall discusses some strategies to lower peroxynitrite
http://www.csom.ca/wp-content/uploa...g-was-Right-but-for-the-Wrong-Reason-25.3.pdf
may explain why i was helped by mixed tocopherols temporarily
 

Learner1

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@vortex Your analysis of peroxynitrites is very pertinent. I've been working on high peroxynitrites in my own situation.

Peroxynitrites all inhibit complex I of mitochondria, which can lead to devastating health problems and they damage mitochondrial membranes (see attachments) making them less efficient.

In my case, it's resulted in a higher need for methylating nutrients, and increaing glutathione through IV and liposomal glutathione has helped to compensate and increase function. After a recent OAT test showed my vitamin C to be very.low, even though I was taking it, I upped my intake to 9g a day on 3 doses.

To fix the membrane damage, NT Factor, which contains the phospholipid constituents of the membranes and phosphatidyl choline IVs, has been helping as well. Yak8ng the other mito nutrients Nicolson mentions helps too, though I find NAD+ to be better thsn NADH (or NR).

I've attached another Pall paper that goes into more on what he thinks we should do.
 

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I recently read an interesting post on another forum about peroxynitrites role in peripheral neuropathy and it got me thinking if this could explain the small fibre neuropathy present in some POTS patients.

The post basically showed that when you stop ONOO from forming, you stop peripheral neuropathy, and when you increase ONOO you increase neuropathy. It seems to work by the ONOO reacting with the tyrosine side chains of the microtubules. It does this easier on nerves that are poorly myeliated (SFN?).

The post goes on to say that progesterone, pregnenolone, and gama-tocopherol should have a protective effect via stabilizing and myelinating the tubules, and binding with ONOO. This is interesting as I noticed improvement in some POTS symptoms when using DHEA and Pregnenolone, however it had some bad effects on libido and other issues causing me to stop.

It also says how things like methylene blue can cause worsening neuropathy by increasing ONOO (MB increases super oxide formation causing more NO to turn into ONOO). Interestingly enough I was on MB when a drastic worsening of my POTS occurred.

What do you think @Learner1 ?
I'm trying methylene blue based on symptoms of mine pointing toward lactic acid/carbon dioxide problems, but very cautiously because of your post here. Could you point me toward that post? What does haidut think of this idea? I tend to think he does his research pretty thoroughly and so I trust his judgment
 
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I'm trying methylene blue based on symptoms of mine pointing toward lactic acid/carbon dioxide problems, but very cautiously because of your post here. Could you point me toward that post? What does haidut think of this idea? I tend to think he does his research pretty thoroughly and so I trust his judgment
Part of why I'm curious is that methylene blue is often touted by that crowd as broadly protective
 

sb4

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I'm trying methylene blue based on symptoms of mine pointing toward lactic acid/carbon dioxide problems, but very cautiously because of your post here. Could you point me toward that post? What does haidut think of this idea? I tend to think he does his research pretty thoroughly and so I trust his judgment
Here it is mate. You'll have to scroll up a bit. It is by user Travis. He is a bit ... err extravagant, but his chemistry seems to be solid and he has some interesting ideas.
 
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"It could be folly to assume that peripheral neuropathy and pigmentation ought to converge towards the same causal factor. These two symptoms could very well be etiologically unrelated despite their temporal association. I would even go so far as to say that they are quite distinct, and that all cases of peripheral neuropathy reduces down to one molecule. I have inferred this before, yet I have now found confirmation of this. Consider the following:

Stavniichuk, Roman. "Peroxynitrite and protein nitration in the pathogenesis of diabetic peripheral neuropathy." Diabetes/metabolism research and reviews (2014)
'Accumulation of nitrotyrosine, a product of peroxynitrite-induced protein nitration, has been documented in peripheral nerve [31], vasa nervorum [7–9] and dorsal root ganglion [32] in streptozotocin diabetic rats, and peripheral nerve, spinal cord and dorsal root ganglion of streptozotocin diabetic and ob/ob mice [31,33–35] indicating that diabetes creates not just oxidative but oxidative/nitrosative stress in the peripheral nervous system.' ―Stavniichuk

'Our findings implicate both peroxynitrite injury in toto and its component, protein nitration, in the development of advanced diabetic peripheral neuropathy; they also suggest that protein nitration does not account for all detrimental effects of peroxynitrite, and that peroxynitrite, the most potent oxidant in biological systems, contributes to the development of diabetes-associated neuropathic changes through both protein nitration and oxidative stress.' ―Stavniichuk

'Our findings indicate that both peroxynitrite injury in toto and its component, protein nitration, play an important role in the development of chronic diabetic peripheral neuropathy. [...] Treatment with a peroxynitrite decomposition catalyst alleviated peripheral nerve dysfunction and increased intraepidermal nerve fibre density, whereas a protein nitration inhibitor resulted in a significant improvement of functional indices only.' ―Stavniichuk

Janes, Kali. "Bioenergetic deficits in peripheral nerve sensory axons during chemotherapy-induced neuropathic pain resulting from peroxynitrite-mediated post-translational nitration of mitochondrial superoxide dismutase." PAIN (2013)
'This chronic neuropathy is characterized by bilaterally symmetrical sensory symptoms (eg numbness, tingling, and pain) appearing in the feet, or in both the feet and hands [49], and occurs with chemotherapeutics across drug classes with distinctly different anti-tumor mechanisms, such as taxanes (eg paclitaxel), platinum-complexes (eg oxaliplatin), and proteasome-inhibitors (eg bortezomib). Recent work in rats indicates a common pathophysiology for CIPN from these agents due to a long-lasting dysfunction in mitochondria of peripheral nerve sensory axons (PNSAs) [51,53,55,56] that can be blocked by mitoprotective agents, such as acetyl-L-carnitine [53,56] and olesoxime [52], and exacerbated by mitochondrial poisons [51].' ―Janes

'The triggering mechanisms of this mitotoxicity are unknown, but the potent nitroxidative species peroxynitrite (PN) may play a critical role. We have recently reported that PN contributes to the development of paclitaxel-induced neuropathic pain and that administration of a peroxynitrite decomposition catalyst (PNDC) can prevent this mechano-hypersensitivity [12]. Protein nitration by PN, the product of superoxide (SO) and nitric oxide (NO) [4], in pathological settings can lead to gain or loss of protein function [17].' ―Janes

'Here we confirm our recent findings that PN is a critical determinant of paclitaxel-induced neuropathic pain [12] and now extend to CIPN observed with two other distinct chemotherapeutic agents: oxaliplatin, which is used for metastatic colon cancer and other gastrointestinal tumors, and bortezomib, which is used for multiple myelomas [13].' ―Janes
Peroxynitrite (ONOO⁻) is formed by the spontaneous union of nitric oxide (ṄO) and superoxide (Ȯ₂⁻). Although not a free radical like its' substrates, peroxynitrite is actually more dangerous and characteristically adducts with tyrosine side-chains on proteins. Although Kali Janes assumes above that peroxynitrite-induced neuropathy occurs upon tyrosyl nitration of mitochondrial proteins, this assumption fails when noting the persistence of neuropathic symptoms greatly outlasts the mitochondrial turnover rate. I think it is more reasonable to assume the nerve proteins themselves are the targets, and specifically α- and β-tubulin: The subunits of long microtubule fibers invariably found at the centre of every nerve. Mitochondrial theories also fail to account for the reductions in nerve velocity noted.

Methylene blue predictably lowers the concentration of nitric oxide (ṄO), yet does so by increasing superoxide (Ȯ₂⁻). Although the resulting product—peroxynitrite (ONOO⁻)—is not a free radical like its' substrates, it is more dangerous on account of tyrosyl nitration. Although nitric oxide is most well-known: nitrogen dioxide (ṄO₂), nitrosonium (NO⁺), and peroxynitrite (ONOO⁻) are considered to be the most dangerous reactive nitrogen species. Methylene blue lowers nitric oxide by converting it into a more dangerous product.

Wolin, Michael. "Methylene blue inhibits vasodilation of skeletal muscle arterioles to acetylcholine and nitric oxide via the extracellular generation of superoxide anion." Journal of Pharmacology and Experimental Therapeutics (1990)
'Since a reduced form of methylene blue can generate superoxide anion (McCord and Fridovich, 1970) and tissues contain enzymes known to reduce methylene blue (Thunberg, 1930), the generation of superoxide anion could be involved in the inhibitory actions of methylene blue.' ―Wolin

'The inhibition of vasodilation to 0.01 μg acetylcholine by methylene blue of 66 ± 13% was completely prevented by suffusion of superoxide dismutase, whereas the inhibitory action of methylene blue was not altered in the presence of catalase.' ―Wolin

'Methylene blue is generally assumed to be an inhibitor of the activation of the soluble form of guanylate cyclase, however, recent evidence suggests that this assumption may not be completely accurate.' ―Wolin

'Since it is currently thought that all of these agents produce vasodilation through the activation of soluble guanylate cyclase via the formation of nitric oxide (Ignarro, 1989), methylene blue, at the concentration used, does not appear to function as an inhibitor of guanylate cyclase activation in the cremaster microcirculation. The reversal of the action of methylene blue by topical suffusion of superoxide dismutatase, but not by catalase, suggests that methylene blue inhibits the action of vasodilators through the extracellular generation of superoxide anion.' ―Wolin

'The effects of methylene blue on rat cremasteric arteriolar diameter are most consistent with an increased generation of extracellular superoxide anion, since the actions of this probe are antagonized by suffusion or extracellular application of superoxide dismutase.' ―Wolin

'A reduced form of methylene blue can generate superoxide anion (McCord and Fridovich, 1970), however, the mechanism of generation of this oxygen species has not been extensively examined.' ―Wolin

'It has been known since the early 1900s that many dehydrogenase enzymes present in mammalian tissues can reduce methylene blue and that the reduced form is readily oxidized by oxygen (Thunberg, 1930). Thus, methylene blue should be readily reduced by enzyme activities present in the cremaster microcirculation and the levels of superoxide anion generated by its auto-oxidation could conceivably be dependent on the tissue oxygen tension and superoxide dismutase activity. Since superoxide dismutase completely reverses the actions of methylene blue, an intracellular effect of methylene blue-elicited generation of superoxide anion is not detectable under the present conditions.' ―Wolin

The enzymes most influential on peroxynitrite concentrations are nitric oxide synthase, superoxide dismutase, and cyclooxygenase. As can be gathered from the study above, superoxide dismutase converts superoxide (Ȯ₂⁻) into the less-harmful hydrogen peroxide (H₂O₂) or water (H₂O). Nitric oxide synthase comes in three related forms (iNOS, eNOS, nNOS), and is responsible for transforming arginine into nitric oxide (ṄO) and citrulline. Cyclooxygenase lowers peroxynitrite concentrations by using it in prostaglandin H formation, creating its' characteristic endoperoxide bridge through peroxynitrite's (ONOO⁻) peroxy moiety (–OO⁻). Peroxynitrite is actually the other substrate besides the 3 known lipids—i.e. dihomo-γ-linolenic, arachidonic, eicosapentaenoic—for prostaglandin H, and thus for all subsequent prostaglandins (Landino, 1996).



Superoxide dismutase activity has consistently been shown to lower both superoxide and peroxynitrite, an enzyme also been shown to attenuate peripheral neuropathy; this is fully-consistent with peroxynitrite being the causal factor. Since peroxynitrite has another precursor besides superoxide contributing approximately half its molecular weight, a person could infer that the inhibition of nitric oxide synthase might also lower peroxynitrite synthesis and peripheral neuropathy. Indeed, this has been tested and confirmed in mice genetically-engineered to lack inducible nitric oxide synthase (iNOS⁻):

Vareniuk, I. "Inducible nitric oxide synthase gene deficiency counteracts multiple manifestations of peripheral neuropathy in a streptozotocin-induced mouse model of diabetes." Diabetologia(2008)
'Diabetic distal symmetric sensorimotor polyneuropathy affects ~50% of patients with diabetes mellitus, and is a leading cause of foot amputation [1]. Evidence for the important role of the highly reactive oxidant peroxynitrite [2,3] in peripheral diabetic neuropathy is emerging from both experimental [4-7] and clinical [8-10] studies. Accumulation of nitrotyrosine, a footprint of peroxynitrite injury, has been found in peripheral nerve, vasa nervorum, spinal cord and dorsal root ganglion neurons in animal models of both type 1 and type 2 diabetes [3-7,11-13] and high glucose-exposed cultured human Schwann cells [14].' ―Vareniuk

'Clinical studies revealed increased plasma nitrotyrosine levels and their correlation with endothelial dysfunction and redistribution of sudomotor responses, an early sign of sympathetic nerve dysfunction, in type 1 diabetic patients [8-10]. Furthermore, plasma peroxynitrite generation assessed by the pholasin chemiluminescence test correlated with the diabetic neuropathy impairment score of the lower limbs [10].' ―Vareniuk

'Nitrated tyrosine immunofluorescence was increased by 69% in the sciatic nerves of diabetic wild-type mice compared with non-diabetic controls. In contrast, no diabetes-induced nitrotyrosine accumulation was detected in the sciatic nerves of iNos⁻ mice.' ―Vareniuk



'Diabetic wild-type mice displayed peroxynitrite injury in peripheral nerve and dorsal root ganglion neurons. They also developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia and ~36% loss of intraepidermal nerve fibres. Diabetic iNos⁻ mice did not display nitrotyrosine and poly(ADP-ribose) accumulation in peripheral nerve, but were not protected from nitrosative stress in dorsal root ganglia. Despite this latter circumstance, diabetic iNos⁻ mice preserved normal nerve conduction velocities.' ―Vareniuk



'Inducible NOS plays a key role in peroxynitrite injury to peripheral nerve, and functional and structural changes of diabetic neuropathy. Nitrosative stress in axons and Schwann cells, rather than dorsal root ganglion neurons, underlies peripheral nerve dysfunction and degeneration.' ―Vareniuk

By lowering the concentration of either of the two peroxynitrite precursors, peripheral neuropathy is predictably attenuated. This is presumed to be caused by peroxynitrite and correlates with nitrotyrosine concentration, nerve conduction velocity, and the sensitivity of mice feet towards heat.

Microtubules are tubular structures residing within the center of myelinated and unmyelinated nerves, long polymers of alternating α- and β-tubulin monomers of indefinite length. Due to their locality and structure, it's hard to imaging that any structure besides could be responsible for long-distance nerve conduction. In the lumen of microtubules are repeating arrays of the aromatic side-chains of tryptophan, histidine, phenylalanine, and tyrosine—the canonical target of peroxynitrite. Peripheral nerves are less-myelinated and would be the most vulnerable to tyrosyl nitration, a process that could even occur to nascent tubulin in the cytosol before it's addition to microtubule ends. Kali Janes' mitochondrial theory of peroxynitrite-induced neuropathy also fails to account for its' the peripheral nature of the neuropathy because mitochondria are found everywhere.

Under this paradigm, methods to induce or inhibit peripheral neuropathy suggest themselves. Progesterone and γ-tocopherol would likely inhibit protein nitration by myelinating nerves and adducting-with peroxynitrite (Christen, 1997). Both free iron and methylene blue have been shown to increase both superoxide & peroxynitrite concentrations, and cyclooxgenase inhibitors might increase peroxynitrite affinity for tyrosine by inhibiting it's conjugation to lipids."


Posting this here because people may find it helpful, very detailed comment by a user on another forum
 
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"There is actually an article in I think in . . . Medial Hypothesis that describes a 'Peroxynitrite Theory of Chronic Fatigue.' I didn't really like it because I don't think peroxynitrite can logically explain fatigue, its' defining symptom, yet the fact that it had been published does imply there is an actual link. More insight into peripheral neuropathy can be gained by looking into the side-effects of colchicine, the classic microtubule inhibitor also used clinically for gout. Colchicine is very effective in vitro at depolymerizing microtubules, or our 'inner nerves,' and occurs both in purified chemical systems and cell culture. Colchicine is the canonical microtubule depolymerizer, and so much so that tubulin has an official 'colchicine binding site.' Colchicine reliably induces peripheral neuropathy and judging by it's mechanism of action, and its side-effects, I'd assume non-myelinated microtubules must also be targets in vivo. 'Colchine' is essentially synonymous with 'microtubule destabilization.' [There are literally thousands of microtubule + colchicine studies, but here are a few:]
[1] Uppuluri, Shobha. "Localization of the colchicine-binding site of tubulin." Proceedings of the National Academy of Sciences (1993)

[2] Lu, Yan. "An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site." Pharmaceutical Research (2012)

[3] Jung, Hyo. "Colchicine activates actin polymerization by microtubule depolymerization." Molecules & Cells (1997)

[4] Chang, Ed. "Developing a model of Colchicine neuropathy." Microsurgery (2002)

I have just found-out that 'taxol neuropathy' is also a very common occurrence. This is quite relevant because taxol is the canonical microtubule stabilizer. I consider taxol in this sense to a phytochemical analogue of pregnenolone, the steroid which binds microtubules with the highest affinity. Progesterone and pregnenolone are prime constituents of myelin, and judging by their affinities for tubulin I'd assume they're the first laid-down. So notorious is taxol in binding microtubules that I wouldn't be surprised if tubulin had an official 'taxol binding site,' and microtubule stabilization is actually this drug's reported mechanism of action. This may initially seem to contradict any microtubule damage theory of peripheral neuropathy, yet once the lowered rate of microtubule turnover is noted it can still hold-up: I think it is quite logical to assume that taxol induces peripheral neuropathy via microtubule hyperstabilization, thereby reducing turnover rates and allowing normal background levels of peroyxynitrite damage to accumulate and manifest. Though pregnenolone, progesterone, and myelin also stabilize microtubules, they are laid-on thicker so they also protect. Taxol can powerfully-stabilize tubulin at a very low molar ratio, and thus can do so at a far lower surface area. I don't think taxol progressive 'stacks' like steroids will during myelinization—like Pringles™—and might even prevent microtubule-associated proteins from proper binding.
[5] Schiff, P.B. "Taxol stabilizes microtubules in mouse fibroblast cells." Proceedings of the National Academy of Sciences (1980)

[6] Sahenk, Zarife. "Taxol neuropathy: electrodiagnostic and sural nerve biopsy findings." Archives of neurology (1994)

[7] Nogales, Eva. "Structure of tubulin at 6.5 Å and location of the taxol-binding site." Nature (1995)

[8] Lipton, R. B. "Taxol produces a predominantly sensory neuropathy." Neurology (1989)"
 

Learner1

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"There is actually an article in I think in . . . Medial Hypothesis that describes a 'Peroxynitrite Theory of Chronic Fatigue.' I didn't really like it because I don't think peroxynitrite can logically explain fatigue, its' defining symptom, yet the fact that it had been published does imply there is an actual link.
See the attachments where mitochondrial impairment is due to peroxynitrites.
I have just found-out that 'taxol neuropathy' is also a very common occurrence. This is quite relevant because taxol is the canonical microtubule stabilizer. I consider taxol in this sense to a phytochemical analogue of pregnenolone, the steroid which binds microtubules with the highest affinity. Progesterone and pregnenolone are prime constituents of myelin, and judging by their affinities for tubulin I'd assume they're the first laid-down. So notorious is taxol in binding microtubules that I wouldn't be surprised if tubulin had an official 'taxol binding site,' and microtubule stabilization is actually this drug's reported mechanism of action. This may initially seem to contradict any microtubule damage theory of peripheral neuropathy, yet once the lowered rate of microtubule turnover is noted it can still hold-up: I think it is quite logical to assume that taxol induces peripheral neuropathy via microtubule hyperstabilization, thereby reducing turnover rates and allowing normal background levels of peroyxynitrite damage to accumulate and manifest. Though pregnenolone, progesterone, and myelin also stabilize microtubules, they are laid-on thicker so they also protect. Taxol can powerfully-stabilize tubulin at a very low molar ratio, and thus can do so at a far lower surface area. I don't think taxol progressive 'stacks' like steroids will during myelinization—like Pringles™—and might even prevent microtubule-associated proteins from proper binding.
It's more than that. Paclitaxel damages mitochondria in other ways.

Paclitaxel induces the opening of the mitochondrial permeability transition pore in axons followed by mitochondrial membrane potential loss, increased reactive oxygen species generation, ATP level reduction, calcium release and mitochondrial swelling.
Peroxynitrite accumulation is a big possibility.
I'm one of the only cancer survivors I know who had paclitaxel but is not left with neuropathy in my feet. My naturopath had me on oral NAC and IV. glutathione throughout my treatment.

Also, most patients getting paclitaxel are typically on it for female cancers and are typically taken off all hormones, during treatment.

very good blog by cort on this topic.
I'm glad this discussion is happening, but find it frustrating that trearments, which have already been developed, are not being discussed.

I found I have peroxynitrites still - my doctors and I have measured nitrotyrosine, we've found my mitochondrial function has been impacted (impaired complex I, complexes II-IV spewing out free radicals making more peroxynitrites), depleted glutathione, depleted manganese, depleted riboflavin, etc.) And realized that I have a bunch of SNPs that point toward low SOD production, increased peroxynitrite production and lousy membrane repair.

I've been on a the nutrients Pall and Nicolson suggested in tbe attached and a phospholipid replenishment program, including Nicolson's NT Factor and phosphatidyl choline IVs. And, my function has improved since starting...

So, I agree with the premise of this thread, that peroxynitrites are more involved than realized.
 

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Just wanted to bump this thread. Palls work on EMF and oxidative stress/dna damage is interesting.
@Learner1 would you thhink that Mountain View is open to these ideas or did you have to work with your naturopath mostly ?

The whole barrage of Mito function tests sounds important but expensive.

Would love to try NAD+ ivs.

Would you recommend a Pall book that has theory but also some practical recommendations?

The ion channel stuff and channelopathies seems to connect this oxidative stress theory to T1am theory/theories that emphasize importance of intracellular calcium.
 
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One more thing— can one have reductive stress (like pyruvate—lactate reduction /aerobic glycolysis) and have oxidative stress? I would assume that the whole body doesn’t just have one redox state and that different bodily systems can have different ones but idk.