PD and vitamin B12 - cyanide and substantia nigra

[aspergerian]

PD and vitamin B12

Introduction

A 2018 study reported that vitamin B12 alters pathologic variants of alpha-synuclein (1). My possible trial of high-dose B12 prompted the realization that I ought research B12 more thoroughly. Regarding vitamin B12 supplement use by individuals with Parkinson's, the softness of a 2019 study's findings (2) may have resulted from the researchers and statisticians not considering the possibility of PWPs having suboptimal levels of glutathione (GSH). For such individuals, ingesting cyanocobalamin may have induced cyanide-related adverse effects which diluted findings the researchers delineated.

Summary: cyanocobalamin is quite common and is regarded as "safe". However, it breaks down into cobalamin and cyanide (3). The persistent notion is that it's just a low level. However, findings in some studies suggest that "safely low level" of cyanide may not be true for all individuals, particularly persons with Parkinson's.

For instance, GSH particulates in detoxification of cyanide (4-5). GSH is suboptimal in many PWPs, even in parts of the brain affected in PD. Indeed, cyanide is attracted to the Substantia nigra (6-9).

Bottom line: There may be a subgroup of individuals for whom ingesting cyanocobalamin may induce at least some pathological changes in neurons affected in PD.

PD, B12, glutathione, cyanide, cyanocobalamin

Vitamin B12 inhibits α-synuclein fibrillogenesis and protects against amyloid-induced cytotoxicity.

2018.

ncbi.nlm.nih.gov/m/pubmed/3...

[TCB] In humans, molarity needed to lessen alpha-synuclein probably not achievable.

[TCB] A 2019 study of B12 ingestion patterns and effects (2019). Some benefit noted.

2. Characterization of Vitamin B12 Supplementation and Correlation with Clinical Outcomes in a Large Longitudinal Study of Early Parkinson’s Disease.

2019.

"We stratified subjects into 4 groups according to daily supplement use: no B12, multivitamin (MVI) containing < 100 μg B12, B12 ≥ 100 μg, and MVI + B12 ≥ 100 μg."

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

[TCB] Cyanocobalamin metabolizes to cobalamin and cyanide.

3. Comparative Bioavailability and Utilization of Particular Forms of B12 Supplements With Potential to Mitigate B12-related Genetic Polymorphisms.

2017.

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

[TCB] Glutathione (GSH) participates in detoxification of cyanide.

4. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia.

2016.

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

5. Cyanide-induced Death of Dopaminergic Cells is Mediated by Uncoupling Protein-2 Up-regulation and Reduced Bcl-2 Expression.

2009.

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

[TCB] GSH is low in many PwPs.

6. Alterations in the distribution of glutathione in the substantia nigra in Parkinson's disease.

1997.

ncbi.nlm.nih.gov/pubmed/944...

[TCB] Cyanide injures neurons affected in PwPs.

7. Cyanide-induced Death of Dopaminergic Cells is Mediated by Uncoupling Protein-2 Up-regulation and Reduced Bcl-2 Expression.

2009.

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

8. Cyanide-Induced Apoptosis of Dopaminergic Cells Is Promoted by BNIP3 and Bax Modulation of Endoplasmic Reticulum-Mitochondrial Ca2 Levels.

2010.

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

9. Cyanide‐induced neural dysfunction and neurodegeneration.

2015.

onlinelibrary.wiley.com/doi...

My multivitamin and my B Complex 100 each contain cyanocobalamin. B12 other than cyanocobalamin ought be used in B12 boost.

****

Additional readings.

2017 findings of Laurie Mischley et al were obtained by a "new" methology relevant to diverse populations with diverse, untested SNPs, and a variety of cultural habits and personal choices.

Role of Diet and Nutritional Supplements in Parkinson's Disease Progression.

Laurie Mischley 2017.

ncbi.nlm.nih.gov/pubmed/290...

****

Excellent summary of mitochondrial concerns and therapuetic opportunities:

B12 patent : US Patent for Cyanocobalamin, methylcobalamin, and/or adenosylcobalamin to help maintain a pain-free head and pain-free body and provide defense against headaches and body pain Patent (Patent # 9,855,292 issued January 2, 2018) [treating mitochondria] - Justia Patents Search.

patents.justia.com/patent/9...

Fascinating!

patents.justia.com/patent/9...

Excerpts:

[Safety]

All other headache remedies with adequate research proving their efficacy have safety profiles that contrast sharply with cyanocobalamin, methylcobalamin, and adenosylcobalamin which are considered by the nutritionists and the FDA to have excellent safety profiles, they are so safe and vital to health, that—like exceedingly few other products—they are recommended to women who are pregnant and lactating!

[Relevance to mitochondria]

A non-obvious mechanism of action disclosed in the current invention is that increased mitochondrial concentrations of adenosylcobalamin (and also coenzyme Q10, magnesium, L-carnitine, and riboflavin) prevent or lessen the severity of a cellular energy crisis in which mitochondrial function declines. Such a decline can be due to alternating inner membrane potential, imbalanced trans-membrane ion-transport, and an overproduction of free radicals. (Zhuo M L, Huang Y, Liu D P, Liang C C (April 2005). “KATP channel: relation with cell metabolism and role in the cardiovascular system”. Int. J. Biochem. Cell Biol. 37 (4): 751-64.)

In such a situation, mitochondrial K(ATP) channels open and close to regulate both internal Ca2+ concentration and the degree of membrane swelling. This helps restore proper membrane potential, allowing further H+ outflow, which continues to provide the proton gradient necessary for mitochondrial ATP synthesis. Without aid from the potassium channels, the depletion of high energy phosphate would outpace the rate at which ATP could be created against an unfavorable electrochemical gradient. (Xu M, Wang Y, Ayub A, Ashraf M (September 2001). “Mitochondrial K(ATP) channel activation reduces anoxic injury by restoring mitochondrial membrane potential”. Am. J. Physiol. Heart Circ. Physiol. 281 (3): H1295-303.)

An ATP-sensitive potassium channel is a type of potassium channel that is gated by ATP. Simply stated, levels of ATP influence constriction and dilation of blood vessels which have receptors for ATP known as P2x-R. Many vascular headaches, including migraine, begin with a brief vasoconstriction immediately followed by vasodilation, resulting in a throbbing headache. The current invention therefore surprisingly prevents headaches by providing the micronutrients needed for the mitochondria to function properly.

Any shortage or deficiency of adenosylcobalamin and/or the other micronutrients disclosed in the current invention will impair or inhibit mitochondrial functioning. Additionally, increasing amounts of adenosylcobalamin and/or the other micronutrients disclosed herein will accelerate the chemical reactions in the mitochondria, thereby permitting the mitochondria to metabolize more chemical energy over a given period of time.

One example of the utility of the current invention is its amelioration of mitochondrial dysfunction in the hypothalamus, a hormone secreting region of the brain which is associated with cluster headaches.

One especially preferred embodiment of the current invention is a once-daily dissolving that is placed on the tongue and swallowed, and contains combinations of cyanocobalamin, methylcobalamin, and adenosylcobalamin in amounts that are effective in defending the individual against headache and body pain; and the current invention also includes one or more of the following substances or metabolites and salts thereof: magnesium, coenzyme Q10, L-carnitine, and riboflavin.

[Patent document continues]

Magnesium ions are important to the production of nucleic acid, DNA, and RNA, and the catalytic action of many enzymes....

Proper functioning of the mitochondria requires coenzyme Q10 (CoQ10), also known as ubiquinone or 1-4-benzoquinone....

Riboflavin (vitamin B2) has an important function in energy metabolism....

Levocarnitine (or L-carnitine) plays an important role in energy metabolism by helping the transport of fatty acids from the cytosol into the mitochondria. Also, it helps remove toxic chemical byproducts from the mitochondria so they do not accumulate....

**** eof ****

[jimcaster]

Lots of great information. Thank you! I take 2,000 mcg of methylcobalmin per day...approximately 830 times the recommended daily value for B12. Of all the supplements I take, it's the one which made me immediately feel better beginning the first day I took it.

[marcet in reply to jimcaster]

Could I ask what brand you use ?

[jimcaster in reply to marcet]

apexenergetics.com/super-me...

[park_bear]

Why not consider instead methylcobalamin or adenosylcobalamin? Neither contain cyanide. Adenosylcobalamin has been shown to be helpful for genetically caused PD.

[aspergerian in reply to park_bear]

I have begun methylcobalamin injections. I am stunned by the respected companies that use cyanocobalamin in multivitamins and B Complex products.

[park_bear in reply to aspergerian]

Likewise they use inactive forms - folic acid instead of methyl folate and pyridoxine instead of pyridoxal-5-phosphate (B6). Both of these can end up being toxic due to occupying receptors intended by evolution to accept the active forms.

[ElliotGreen]

My sublingual vitamin B12 supplement has 500 µg of methylcobalamin and 500 µg of adeosylcobalamin. So I guess at least I'm not poisoning myself with cyanide.

[aspergerian in reply to ElliotGreen]

Wise choice. Brand?

[ElliotGreen in reply to aspergerian]

Cytoplan

[silvestrov]

The relationship between B12 and cyanide is fascinating and illuminates the safety of B12.

If you go to a Drs office for a B12 injection, you will receive a monthly 1 mg injection of cyanocobalamin or hydroxocobalamin. If you are unfortunately enough to be in a house fire and have smoke inhalation you have cyanide poisoning. The EMT's will pull out a 'cyanokit,'

cyanokit.com/

A cyanokit is 5,000 mgs of hydroxocobalamin given intavenous in a 15 minute period. That is equivalent to a 417 year supply of doctor's monthly injections in 15 minutes. If you have a real bad case of cyanide poisoning another cyano kit will be given in 1 1/2 to 2 hours. So in a 2 hour period you are receiving 833.33 years of B12 (with transient side effects).

What happens is the hydroxocobalamin binds with the cyanide and is urinated out as cyanocobalamin.

Here is a great article about the safety of high dose B12:

stichtingb12tekort.nl/weten...

Mind you there is no upper scientific limit for B12 and I think it is the safest supplement/drug I have ever investigated.

I have been a big advocate of sublingual methylcobalamin/adenosylcobalamin and, in this case, bigger is truly better.

[silvestrov]

The following article notes that when cyanocobalamin, CN-Cbl, is exposed to light it is converted into hydroxocobalamin.

Hydroxocobalamin association during cell culture results in pink therapeutic proteins

"CN-Cbl levels were significantly reduced upon light-exposure within a single day, and 50% or greater loss was seen over 10 d."

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

The article notes the light conversion effect of cyanocobalamin to hydroxocobalamin is considered a byproduct of the manufacturing process. Why not crush up cyanocobalamin and expose it to light for 10 + days to intentionally make it into hydroxocobalamin?