Peripheral Neuropathy, Rapidly Receding Gums + Bloods

[PhilParma]

I no longer believe my problems are vitamin A related. The things that almost certainly exacerbate my neuropathy and gum recession symptoms are: sunlight and caffeine.

A few weeks ago I quickly weened off of caffeine. I took in no caffeine for 2 or 3 weeks. I became horribly depressed, slept way too much, lost my motivation and will to live, etc. I wasn't going outside much. My gums started to heal, and my neuropathy lessened substantially. This week I started drinking 1 cup of coffee in the morning. I feel much better mentally, but my gums collapsed again. Neuropathy is back a bit as well.

Increased motivation has been my number 1 health goal for years, but it seems like anything dopaminergic ends up having a negative impact on my physical health.

@Travis I don't fully understand your posts in this thread, but you mentioned tyrosine a few times. Can you see a tyrosine/dopamine/sunlight path to neuropathy?

Just a stupid question: i know it seems like the hand and foot numbness issues are related. But have you definitely ruled out ill-fitting shoes?

Everyone I talk to about this asks me that. :) It's not a shoe problem as far as I can tell. I've gone out in sandals, and the neuropathy still reared its head.

I suspect a methylation issue with your B12 -

Can you please tell me more about this? Or point me to an article. I don't know anything about methylation. Most of the information online about peripheral neuropathy online pertains to diabetes or B12, so you could be onto something. My B12 is high-ish.

 

[Travis]

@Travis I don't fully understand your posts in this thread, but you mentioned tyrosine a few times. Can you see a tyrosine/dopamine/sunlight path to neuropathy?

Yes: the classic reaction of peroxynitrite is with tyrosine, forming nitrotyrosine. Having higher concentrations of phenols—i.e. tyrosine, dopamine, epinephrine—within the cells could safely bind more peroxynitrite, reducing the amount available to react with nascent tubulin. Melatonin reduces superoxide concentrations in a number of ways.

Caffeine could increase superoxide generation via xanthine oxidase, as it's known to do. I don't think peripheral neuropathy can exist without either a microtubule depolymerizer such as colchicine, the peroxynitrite ion (ONOO⁻), or perhaps a microtubule stabilizer such as taxol acting to inhibit microtubule turnover ('treadmilling.')

Vitamin C and vitamin E can safely assimilate the free radical electron on superoxide (Ȯ₂⁻), transforming it back into dioxygen (O₂).⁽¹⁾ Mixed tocopherols would also contain γ-tocopherol, proven to actually adduct-with peroxynitrite itself.⁽²⁾ Ascorbic acid also has a classic role in promoting collagen synthesis, capable of increasing the production rate of procollagen 6-fold within 30 minutes.⁽³⁾ Vitamin C also regenerates the less-mobile vitamin E, transferring the membrane-bound free radical to the aqueous phase.

[1] Gotoh, Naohiro. "Rates of interactions of superoxide with vitamin E, vitamin C and related compounds as measured by chemiluminescence." Biochimica et Biophysica Acta (1992)
[2] Hoglen, Niel. "Reactions of peroxynitrite with γ-tocopherol." Chemical research in toxicology (1997)
[3] Schwarz, Richard. "Procollagen secretion meets the minimum requirements for the rate-controlling step in the ascorbate induction of procollagen synthesis." Journal of Biological Chemistry (1985)​

 

[danishispsychic]

I no longer believe my problems are vitamin A related. The things that almost certainly exacerbate my neuropathy and gum recession symptoms are: sunlight and caffeine.

A few weeks ago I quickly weened off of caffeine. I took in no caffeine for 2 or 3 weeks. I became horribly depressed, slept way too much, lost my motivation and will to live, etc. I wasn't going outside much. My gums started to heal, and my neuropathy lessened substantially. This week I started drinking 1 cup of coffee in the morning. I feel much better mentally, but my gums collapsed again. Neuropathy is back a bit as well.

Increased motivation has been my number 1 health goal for years, but it seems like anything dopaminergic ends up having a negative impact on my physical health.

@Travis I don't fully understand your posts in this thread, but you mentioned tyrosine a few times. Can you see a tyrosine/dopamine/sunlight path to neuropathy?


Everyone I talk to about this asks me that. :) It's not a shoe problem as far as I can tell. I've gone out in sandals, and the neuropathy still reared its head.


Can you please tell me more about this? Or point me to an article. I don't know anything about methylation. Most of the information online about peripheral neuropathy online pertains to diabetes or B12, so you could be onto something. My B12 is high-ish.

Why Methylation Matters: Part 1 | MegaFood

 

[PhilParma]

Why Methylation Matters: Part 1 | MegaFood

Hmmm, earlier this summer I took a methyl B12 supplement for about a week and it didn't seem to help with any of my symptoms. I'll look into it though. Thanks.

 

[tara]

Hi Phil,
Just some thoughts to add to all the others, if you are wanting more.

- Tyromix (1 drop morning, 1 drop night; afraid to dose any higher without more regular blood testing habit.)

I would be cautious of more too, given your low weight and symptoms. May be some deficiency/ies at play?

- Carrots w/ Apple Cider Vinegar (3-4 times per week)

I had to rinse grated carrots till the water ran clear to be able to tolerate carrot salad on a regular basis. If you've had orange tinge to skin, you could try that too?

I feel like the grocery store brand concentrated OJ that I was drinking was making things worse.

I eventually got averse to the commercial OJ I was drinking, and started to not feel well if I drank much of it. I eat fresh oranges happily now, but only drink a little of the OJ these days. I'm also eating more other fresh fruit.

Vit C from some source is important for any maintenance and healing. Ideally it would be good to get enough from food, but if that's not possible, or if the demands are high, then maybe there's a case for supplementing? There seem to be pros and cons on this.

Have you tried adding weekly liver?
What about some regular leafy greens, or at least broth?
Could you add in more varied fruits and veges to get a wider range of minerals?
Maybe a bit more seafood, also for minerals?
I suffered when I let simpler sugars displace too much starch. I seem to do better with some of each. Potatoes, other roots, etc. Have you observed whether you do better if you have some potatoes every day?

@Jennifer , I don't like the idea of herbs, but I'm starting to rinse with baking soda, which is something I haven't been doing lately. I'm giving up oil pulling as it doesn't seem to be helping much. Thanks for your reply. Also, I ordered some saliva ph strips yesterday.

I was going to suggest checking UpH as another angle. I think they say at least 2 hours after a meal is best, but not first thing in the morning, and probably a few times to get a pattern. Both Peat and Carey Reams were in rough agreement on healthy/healing range (~6.2/6.3- 6.7/6.8). Maybe you can use the same strips to test?
I think systemic pH affects what you can get out of your food, and what you can do with it.

I've been eating sourdough bread throughout the day for the past month. I feel like it instantly affects my gums negatively. But I keep eating it because I'm underweight and I don't know what else to eat.

I reluctantly stopped eating the delicious long-leavened bread I was baking a while ago. I had to face that it wasn't doing me good. Even though it was easy and delicious and I didn't want to lose more weight. I can't say whetehr it is doing you good or not, but it might be worhth seeing if you can try replacing it for a few days.
For me, that means more potatoes, sweet potatoes, other roots and veges, some rice, fruits, dried fruits, etc for carbs. (Though I'm not sure that too much dried fruit serves me either - I might have to replace some of that, too. I't's really portable and convenient, but rough on the teeth.)

A few weeks ago I quickly weened off of caffeine. I took in no caffeine for 2 or 3 weeks. I became horribly depressed, slept way too much, lost my motivation and will to live, etc. I wasn't going outside much. My gums started to heal, and my neuropathy lessened substantially. This week I started drinking 1 cup of coffee in the morning. I feel much better mentally, but my gums collapsed again. Neuropathy is back a bit as well.

Did you try decaf?
Don't know if that would do it for you, but it's not just caffeine in coffee that can make a difference. Travis has documented in detail on other thread. Anti-opioid, IIRC.

 

[energyandstruct]

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)​

This is all interesting to me. since I have CFS and am in a particularly rough flare it's tricky to parse all this for me, but I wonder if there's a reason that methylene blue is viewed as broadly protective. I swear I've seen a few articles on methylene blue helping recovery from stroke or being a good antibiotic, or helping depression. And people claim that it helps with CO2 and excess lactate, and helps with oxidative phosphorylation. So are all these claims unfounded? Is it dose dependent?

There are anecdotal reports that go both ways as far as I can tell. Would you consider it dangerous to experiment with or would you just avoid continuing it if you get negative symptoms, as one would with anything?

 

[energyandstruct]

Yes: the classic reaction of peroxynitrite is with tyrosine, forming nitrotyrosine. Having higher concentrations of phenols—i.e. tyrosine, dopamine, epinephrine—within the cells could safely bind more peroxynitrite, reducing the amount available to react with nascent tubulin. Melatonin reduces superoxide concentrations in a number of ways.

Caffeine could increase superoxide generation via xanthine oxidase, as it's known to do. I don't think peripheral neuropathy can exist without either a microtubule depolymerizer such as colchicine, the peroxynitrite ion (ONOO⁻), or perhaps a microtubule stabilizer such as taxol acting to inhibit microtubule turnover ('treadmilling.')

Vitamin C and vitamin E can safely assimilate the free radical electron on superoxide (Ȯ₂⁻), transforming it back into dioxygen (O₂).⁽¹⁾ Mixed tocopherols would also contain γ-tocopherol, proven to actually adduct-with peroxynitrite itself.⁽²⁾ Ascorbic acid also has a classic role in promoting collagen synthesis, capable of increasing the production rate of procollagen 6-fold within 30 minutes.⁽³⁾ Vitamin C also regenerates the less-mobile vitamin E, transferring the membrane-bound free radical to the aqueous phase.

[1] Gotoh, Naohiro. "Rates of interactions of superoxide with vitamin E, vitamin C and related compounds as measured by chemiluminescence." Biochimica et Biophysica Acta (1992)
[2] Hoglen, Niel. "Reactions of peroxynitrite with γ-tocopherol." Chemical research in toxicology (1997)
[3] Schwarz, Richard. "Procollagen secretion meets the minimum requirements for the rate-controlling step in the ascorbate induction of procollagen synthesis." Journal of Biological Chemistry (1985)​

Travis this is interesting to me as one of the only supplements that helped me was haidut's tocovit. Past a certain point of illness it hasn't helped much but when it did help, it helped quite a few times and noticeable, to the extent that I would take it if I had to go out and do something, despite really being to sick to. I thought it was really odd that mixed tocopherols , which isn't one of peat's mainstays, would help. progesterone also some too

 

[Travis]

This is all interesting to me. since I have CFS and am in a particularly rough flare it's tricky to parse all this for me, but I wonder if there's a reason that methylene blue is viewed as broadly protective. I swear I've seen a few articles on methylene blue helping recovery from stroke or being a good antibiotic, or helping depression. And people claim that it helps with CO2 and excess lactate, and helps with oxidative phosphorylation. So are all these claims unfounded? Is it dose dependent?

There are anecdotal reports that go both ways as far as I can tell. Would you consider it dangerous to experiment with or would you just avoid continuing it if you get negative symptoms, as one would with anything?

I think methylene blue can be helpful because it is a methyl-donor and a one-electron carrier, somewhat like flavin. This latter aspect of course gives it the ability to act as proxy in the electron transport chain, similar to how vitamin K₂ can substitute for coenzyme Q. Yet too many electrons with no place to go can cause side reactions: such as the one-electron reduction of oxygen (O₂) into superoxide (Ȯ₂⁻), a free radical. Superoxide isn't the end of the world because we have superoxide dismutase, an enzyme that converts it either into hydrogen peroxide (H₂O₂) or back into oxygen. Should hydrogen peroxide form, we then have two enzymes to take care of that: both catalase and glutathione peroxidase—a selenoenzyme—will reduce hydrogen peroxide into two water molecules. The ability of selenium to lower the concentration of superoxide and hydrogen peroxide in the cell is often explained because it's indispensable for glutathione peroxidase synthesis.

Vos, Melissa. "Vitamin K₂ is a mitochondrial electron carrier that rescues pink1 deficiency." Science (2012)​

I can see methylene blue acting both as a methyl-donor and catalyst of the electron transport chain; yet under certain concentrations, and those of the aforementioned enzymes, it could potentially create more superoxide than perhaps desirable. Methylene blue is often noted as creating superoxide during in vitro cell studies, but of course you'd have to compare those concentrations with it's pharmacokinetic dispersal to see what you'd expect after oral consumption.

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)​

At the center of every nerve are microtubule proteins running parallel with it under varying degrees of myelination. These are irreducible nervous structures, and their molecular characteristics suggest a prime role in information transfer. In the lumen of every microtubule are repeating arrays of aromatic amino acids—e.g. tryptophan, tyrosine, histidine, phenylalanine—known to transfer information via Förster Resonance Energy, or a 'trapped fluorescence' of sorts. Peroxynitrite is linked to both neuropathy and tyrosine modification, and there are two ways I can imagine it could do this: (1) It could nitrate the tyrosines on the microtubule monomers—e.g. α-tubulin, β-tubulin, γ-tubulin—as their being formed in the cytosol, leading to a nitrated tubulin being incorporated into growing microtubule ends. (2) Peroxynitrite can become protonated and decompose into the hydroxyl radical (ȮH) and the nitrogen dioxide radical (ṄO₂), as it's known to do, with the latter intercalating into unmyelinated microtubule ends and modifying tyrosine in situ. Peroxynitrite is larger and more polar than nitrogen dioxide, making the latter a much better candidate for microtubule infiltration. Based on what I've read about these topics, I think the 'tingle' of peripheral neuropathy is literal nitrotyrosine in the lumen of the microtubule nerve.

Gunaydin, Hakan. "Mechanisms of peroxynitrite-mediated nitration of tyrosine." Chemical research in toxicology (2009)​

 

[Travis]

Travis this is interesting to me as one of the only supplements that helped me was haidut's tocovit. Past a certain point of illness it hasn't helped much but when it did help, it helped quite a few times and noticeable, to the extent that I would take it if I had to go out and do something, despite really being to sick to. I thought it was really odd that mixed tocopherols , which isn't one of peat's mainstays, would help. progesterone also some too

Yeah. Vitamin E is one of those supplements that should be good for just about everybody, yet there is just one caveat with that. Large prospective studies giving large doses of α-tocopherol had actually noted an increase in cancer rates,⁽¹⁾ yet I think this makes sense when considering that α-tocopherol inhibits the uptake of γ-tocopherol.⁽²⁾ These two similar membrane-bound antioxidants have different functions, and only γ-tocopherol can adduct-with and remove nitrogen dioxide and peroxynitrite.⁽³⁾ In animal studies: γ-tocopherol is invariably found a bit more cancer-protective than α-tocopherol, and its ability to remove reactive nitrogen species must surely be why. Gamma-tocopherol has been shown to reduce tumor volume 56% in rats while α-tocopherol did nothing.⁽⁴⁾

 

[Mito]

I think methylene blue can be helpful because it is a methyl-donor

Have you come across any studies that suggest methylene blue can act as a methyl donor?

 

[Travis]

Have you come across any studies that suggest methylene blue can act as a methyl donor?

Schirmer, R.H. "Lest we forget you—methylene blue…." Neurobiology of aging (2011)

'Methylene blue is excreted in the urine as a mixture of MB, leucoMB and demethylated metabolites, e.g., azure B and azure A (Gaudette and Lodge, 2005).' ―Shirmer​

Gaudette, N.F. "Determination of methylene blue and leucomethylene blue in male and female Fischer 344 rat urine and B6C3F1 mouse urine." Journal of analytical toxicology (2005)

 

[energyandstruct]

Yeah. Vitamin E is one of those supplements that should be good for just about everybody, yet there is just one caveat with that. Large prospective studies giving large doses of α-tocopherol had actually noted an increase in cancer rates,⁽¹⁾ yet I think this makes sense when considering that α-tocopherol inhibits the uptake of γ-tocopherol.⁽²⁾ These two similar membrane-bound antioxidants have different functions, and only γ-tocopherol can adduct-with and remove nitrogen dioxide and peroxynitrite.⁽³⁾ In animal studies: γ-tocopherol is invariably found a bit more cancer-protective than α-tocopherol, and its ability to remove reactive nitrogen species must surely be why. Gamma-tocopherol has been shown to reduce tumor volume 56% in rats while α-tocopherol did nothing.⁽⁴⁾

I'm very curious about why it stopped really helping much. I mean I keep getting worse and the odd thing is that several people report supplements briefly working and than stopping working in CFS which seems to indicate some disease process that adapts! negatively to treatments, it's very odd...

 

[Travis]

I'm very curious about why it stopped really helping much. I mean I keep getting worse and the odd thing is that several people report supplements briefly working and than stopping working in CFS which seems to indicate some disease process that adapts! negatively to treatments, it's very odd...

I do know that γ-tocopherol has a higher turnover rate because it becomes permanently nitrated, while α-tocopherol can be indefinitely regenerated by vitamin C because as it traps only free radical electrons. From this I would assume that our bodies' have a finite capacity for storing α-tocopherol, 'or limited membrane space,' and this is further evidenced by the longer half-lives of lipid-soluble vitamins in general. Yet α-tocopherol is safe even in high amounts, and only phylloquinone has lower toxicity among lipid-soluble vitamins. Due its complete absence of toxicity, a no observed adverse effect limit for vitamin K had 'not been established' by the IOM.

Chronic fatigue is necessarily enigmatic by definition, as this diagnosis had been created for the 'undiagnosable.' Yet there are many correlates of fatigue and I concentrate on plasma ammonia, 5-methoxytryptophol, and prior doxorubicin use.

 

[energyandstruct]

I do know that γ-tocopherol has a higher turnover rate because it becomes permanently nitrated, while α-tocopherol can be indefinitely regenerated by vitamin C because as it traps only free radical electrons. From this I would assume that our bodies' have a finite capacity for storing α-tocopherol, 'or limited membrane space,' and this is further evidenced by the longer half-lives of lipid-soluble vitamins in general. Yet α-tocopherol is safe even in high amounts, and only phylloquinone has lower toxicity among lipid-soluble vitamins. Due its complete absence of toxicity, a no observed adverse effect limit for vitamin K had 'not been established' by the IOM.

Chronic fatigue is necessarily enigmatic by definition, as this diagnosis had been created for the 'undiagnosable.' Yet there are many correlates of fatigue and I concentrate on plasma ammonia, 5-methoxytryptophol, and prior doxorubicin use.

there are arguments over the diagnostic categorybut it seems overally well defined even if it shares characteristics with other metabolic disorders. there have been some "big data" studies that showed pretty robust findings of lots of low levels of things related to metabolism, not quite specific enough for a diagnostic marker, but pretty decent :Metabolic features of chronic fatigue syndrome (I think this was later replicated pretty well in a follow-up)

 

[Mito]

Yet α-tocopherol is safe even in high amounts,

Although it inhibits the uptake of γ-tocopherol?

 

[Travis]

Although it inhibits the uptake of γ-tocopherol?

Well that cannot really be seen as toxicity, and that effect is annulled by γ-tocopherol. I suppose I'd be fair to say that α-tocopherol is dangerous in high chronic doses along with a low intake of γ-tocopherol and under high RNS conditions, yet an economy of words often precludes such lengthy constructs. Information had been omitted for brevity, true, yet as that had been a continuation of comment #69 I'd assumed it would all be understood. The prospective cancer trials had been years long, and should a person start taking 5× the RDA of α-tocopherol today they would still have a long time of relative safety to consider taking mixed tocopherols as previously suggested.

 

[Arctic Fire]

I was going to suggest checking UpH as another angle. I think they say at least 2 hours after a meal is best, but not first thing in the morning, and probably a few times to get a pattern. Both Peat and Carey Reams were in rough agreement on healthy/healing range (~6.2/6.3- 6.7/6.8). Maybe you can use the same strips to test?
I think systemic pH affects what you can get out of your food, and what you can do with it.

@tara and anyone else: Do you know how to lower urinary pH with diet or lifestyle? Has RP discussed this topic? (I know he's said that happy cells producing plenty of CO2 will be slightly acidic, but I don't recall his discussing what drives UpH.)

 

[PhilParma]

Update:

Based on @Travis's posts I searched "superoxide peripheral neuropathy" and Copper Deficiency came up. So started eating (dessicated) liver and my neuropathy is 99% gone.

 

[sladerunner69]

Update:

Based on @Travis's posts I searched "superoxide peripheral neuropathy" and Copper Deficiency came up. So started eating (dessicated) liver and my neuropathy is 99% gone.

Interesting, I've noticed this as well. My neuropathy and anxiety levels seem to worsen gradually each week until I have liver or oysters, both rich sources of copper. I also noticed that it tightens and smoothens my skin the day after.

 

[Lolinaa]

Update:

Based on @Travis's posts I searched "superoxide peripheral neuropathy" and Copper Deficiency came up. So started eating (dessicated) liver and my neuropathy is 99% gone.

What about your gum? Did you find a solution?