Peripheral Neuropathy, Rapidly Receding Gums + Bloods

[Travis]

That is, greater plasma concentraion [sic] of omega-6 meant better nerve conduction, lower concentration predicted accelerated peripheral nerve decline.

It did, really? Then can you tell us why arachidonic acid is the only fatty acid negatively associated with nerve velocity in the < 65 year age group?

In the same age group: α-linolenic (18∶3ω−3) had been the fatty acid most associated with nerve velocity, just as you'd expect from a DHA precursor. Docosahexanoic acid (22∶6ω−3) itself had been found most associated in the 65–84 year old group, another group in which arachidonic acid was found negatively correlated. Due to only 26 participants, it would be fair to consider the > 85 group far less-reliable than the others.

 

[shepherdgirl]

Great to hear that your neuropathy and orange toes are going away. I actually stopped supplementing vit. A for now based on your possible problems with it.
Gum recession is a frustrating puzzle - maybe there is some clue about how to reverse it in the multiple drugs that have gum hyperplasia as a side effect?

 

[Jennifer]

Have you checked the pH of your saliva, @PhilParma? There's a chance it's acidic. If so, you may want to try raising it. We did this with my dog and completely regenerated his gum tissue. The recession was so bad we could see the roots of his canines, and despite us brushing his teeth regularly, he had thick brown plaque. It all completely resolved after we put him on an herbal tea called Heal All. It contains:

• White Oak Bark
• Plantain Leaf
• Black Walnut Hull
• Chaparral Herb
• Burdock Root
• Marshmallow Root
• Comfrey Root
• Comfrey Leaf

You use the tea as a rinse by holding it in your mouth for 5 minutes at a time. You can then swallow it since it has positive systemic effects. We used to make the tea up in large batches and put it in our dog's food — he consumed a raw diet high in alkaline minerals —mainly ripe fruit, veggies and coconut water, and small amounts of eggs and scallops. If you don't like the idea of herbs, there's also baking soda rinses. I've never tried it before so I can't comment on how well it works.

I hope you find relief soon! :)

 

[Progesterone]

Are you continually using Tyromix, 2 drops a day, without testing temp+pulse throughout the day?

 

[Travis]

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.

 

[PhilParma]

Amazingly informative post @Travis

I'M TAKING METHYLRNE BLUE. Not after that post though. I need any excuse to cut out supplements.

I've associated zinc with progesterone. I will cut out methylene blue and eat weekly oysters for zinc/progesterone.

 

[PhilParma]

Your diet sounds deficient in minerals, certainly copper, iron, molybdenum, zinc, off the top of my head.

I eat oysters and red meat weekly. What could I add to my diet to increase zince, copper, etc? The only thing I can think of is liver.

If you're experiencing neuropathy, see a physician. But if you see a physician, be sure to tell the physician that you're eating a diet prescribed by an Internet Sensation!

As mentioned in my previous post, I saw multiple physicians. I didn't make fun of myself by describing my diet as that of an Internet Sensation, but I mentioned that I eat a high carb, high sugar diet. They didn't seem to care. No doctor I have ever seen cares about diet; if I bring it up, they refer me to a nutritionist.

 

[PhilParma]

Are you continually using Tyromix, 2 drops a day, without testing temp+pulse throughout the day?

Pulse is high 40's to mid 50's upon waking. Mid-day pulse gets as high as 80, but very often settles in the 60s. Pulse at bed time is usually mid 50's.

I don't take temps very often. When I do, it's approximately 97.9 upon waking, 98.5-6 after eating.

@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.

@shepherdgirl I'm going to research drug induced hyperplasia. If nothing else, it should be interesting. Thanks.

Can anyone recommend a good Vitamin D testing site/kit? @Blossom

Thank you all.

 

[SB4]

@Travis I find this very interesting. It has been shown that in some CFS/POTS patients there is small fibre neuropathy. It is also hypothesized that peroxynitrite is elevated in a vicious circle in these patients. I wonder if this is significant.

 

[Spokey]

I've heard fruitarians complaining of similar issues and I wondered why. Since the this symptom looks paradoxically like scurvy and well, fruit should have a lot of Vitamin C. And Keto dieters often complain of similar problems, despite eating a lot of vegetables that also contain vitamin C.

I think there's a connection to both. Vitamin C requires insulin to be transported into cells. Fruit requires relatively little insulin to transport it's sugars into cells, thus the consumption of fruit, while being able to raise serum levels, does not provide the insulin load necessary to move vitamin C. Keto diets obviously don't necessitate a high insulin production.

A solution might be eating some starch or pure glucose.

 

[SB4]

@PhilParma @Travis It is also interesting to note that when I massively declined with my POTS I was on methylene blue.

 

[PhilParma]

A solution might be eating some starch or pure glucose.

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.

 

[Blossom]

Pulse is high 40's to mid 50's upon waking. Mid-day pulse gets as high as 80, but very often settles in the 60s. Pulse at bed time is usually mid 50's.

I don't take temps very often. When I do, it's approximately 97.9 upon waking, 98.5-6 after eating.

@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.

@shepherdgirl I'm going to research drug induced hyperplasia. If nothing else, it should be interesting. Thanks.

Can anyone recommend a good Vitamin D testing site/kit? @Blossom

Thank you all.

I've read that Life Extension has an affordable home test kit. Also toxinless has good information on lab tests.

 

[Jennifer]

I've heard fruitarians complaining of similar issues and I wondered why

Poor quality/unripe fruit might be one reason? I eat a fruitarian diet and don't have any dental problems, but I'm extremely picky when it comes to the ripeness of my fruit. I had major gut inflammation/gastritis prior to the diet and don't handle acids well.

 

[Blossom]

Pulse is high 40's to mid 50's upon waking. Mid-day pulse gets as high as 80, but very often settles in the 60s. Pulse at bed time is usually mid 50's.

I don't take temps very often. When I do, it's approximately 97.9 upon waking, 98.5-6 after eating.

@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.

@shepherdgirl I'm going to research drug induced hyperplasia. If nothing else, it should be interesting. Thanks.

Can anyone recommend a good Vitamin D testing site/kit? @Blossom

Thank you all.

The Vitamin D Council is another option.
Vitamin D Articles, News, & Research | Vitamin D Council

 

[Spokey]

Poor quality/unripe fruit might be one reason? I eat a fruitarian diet and don't have any dental problems, but I'm extremely picky when it comes to the ripeness of my fruit. I had major gut inflammation/gastritis prior to the diet and don't handle acids well.

Possibly, though some of these people are having issues even though they have access to high quality produce so I think individual tolerances and adaptations are involved.

 

[Travis]

@Travis I find this very interesting. It has been shown that in some CFS/POTS patients there is small fibre neuropathy. It is also hypothesized that peroxynitrite is elevated in a vicious circle in these patients. I wonder if this is significant.

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)​

 

[shepherdgirl]

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?

 

[danishispsychic]

I suspect a methylation issue with your B12 -

 

[Spokey]

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.

Sour dough is quite acidic, there's a reason it's sour. You're getting a lot of calories from OJ I notice. I can't speak to the quality of your juice but that habit doesn't agree with everyone. You could try white rice and potatoes with some fat and not eating so frequently. Very frequent & low fat meals never worked for me so I don't do it, and with all the sugar and acid frequent meals is hard on teeth. There's no one size fits all, don't ruin your life trying to fit a prescriptive version of Ray's work into it. Context, remember Ray makes a point of telling us all how important context is.