Nicotinamide Exacerbates Motor Symptoms of Parkinson’s Disease in Mice

[Greenday]

parkinsonsnewstoday.com/201...

Nicotinamide a form of B3 and precursor of NAD+ that is essential for energy production in cells mitochondria, failed to produce neuroprotection in a study with PD induced rats that we're treated with Nicotinamide.

"Contrary to the neuroprotection effect in a former study of a fly model of PD parkinsonsnewstoday.com/201... , Nicotinamide treatment in rats enhanced the death of brain cells and structural brain changes. Also, animals treated with a nicotinamide showed increased rate of motor decline and development of behavioral deficits compared to untreated animals."

Even though nicotinamide treatment increased the expression of several neuroprotective genes, it failed to increase neuroprotection; rather, it exacerbated neurodegeneration.

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Other studies have suggested that Nicotinamide may play both a protective and detrimental role in PD ncbi.nlm.nih.gov/pmc/articl... and this differentiation may be dosage related.

"Cultured stem cell–derived neurons respond positively to supplementation with nicotinamide within a dose range of 5 to 10 mM in vitro, but that a 20-mM dose is highly toxic to all neurons" ncbi.nlm.nih.gov/pubmed/242...

Other studies suggest that excess levels of nicotinamide may cause or exacerbate the symptoms of the Parkinson's disease due to the impaired function of NNMT (Nicotinamide N-Methyltransferase), a protein coding gene.

Levels of nicotinamide- NNMT have been shown to be increased in the cerebrospinal fluid ncbi.nlm.nih.gov/pubmed/111... and within specific neuron populations ncbi.nlm.nih.gov/pubmed/127... of patients with PD, suggesting a role in pathogenesis.

Higher NNMT levels have been proposed to cause an increase in conversion of nicotinamide to N-methyl nicotinamide, structurally related to the toxin MPP+, that selectively destroys dopamine neurons. ncbi.nlm.nih.gov/pubmed/156...

In addition, increased NNMT activity leads to lowered mitochondrial complex 1 activity and impaired mitochondrial function, resulting in neurodegeneration. ncbi.nlm.nih.gov/pubmed/225...

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A double-blinded randomized controlled trial is underway, that studies nicotinamide supplementation in early Parkinson's disease. The study involves 200 patients clinicaltrials.gov/ct2/show....

"During this trial the investigators will determine if nicotinamide riboside delays PD disease progression measured by clinical monitoring tools (MDS-UPDRS).

Patients receiving nicotinamide riboside supplementation will receive a daily dose of 1000mg for the duration of the trial. This trial will also collect biological material from participants to see if nicotinamide riboside supplementation rectifies NAD deficiency and metabolism deficiencies."

Possibly there is a fine line, a dose-depended effect of Nicotinamide, able to induce neuroprotection or neurodegeneration in PD. This trial and future human studies may provide further such evidence.

[jimcaster]

Very interesting and very sobering. I have been taking 1050 mg of TruNiagen per day, trying to more or less replicate the ongoing human study. I've been doing this for several months with no apparent ill effects. I wonder what Joe (Sunvox) thinks about this.

[KERRINGTON in reply to jimcaster]

Ditto for sobering...I've been taking 600 mg daily for debilitating fatigue. It has helped quite a bit, but since I'm very cautious, I'll now take it every other day.

Hand tremor is about the same as before I began TRU N.

[jimcaster in reply to KERRINGTON]

Call me crazy, but I'm sticking with it, at least unless/until Joe (Sunvox) stops or the current human study results are available next year. At least that's my thought for now. I might change my mind in an hour. 😊

[KERRINGTON in reply to jimcaster]

Yes, if you feel fine maybe you have the right dose.

[park_bear in reply to jimcaster]

No you are not crazy. This is not a very convincing study. Nicotinamide failed to protect rats from an artificially induced parkinsonism, created by toxic insult:

"the lactacystin rat model of PD, which recapitulates the formation of neurotoxic accumulation of altered proteins within the substantia nigra to cause progressive dopaminergic cell death. Rats received nicotinamide for 28 days, starting 7 days after unilateral injection of the irreversible proteasome inhibitor, lactacystin, into the substantia nigra. "

[Despe in reply to KERRINGTON]

Same here, Kerrington. My husband is taking 600mg a day with no ill effects that I can detect. Have just ordered it again, and it's not cheap.

[KERRINGTON]

My simpleton guess is that it acts as B1, or any supplement, drug etc does...taking too much, or too little makes everything go haywire.

[Greenday in reply to KERRINGTON]

There are possible similarities

1) A)Thiamine pyrophosphate TDP is a cofactor for enzymes involved in the pyruvate and citric cycle and indirectly involved via multiple pathways in the production of ATP, that provides the energy utilized in cells mitochondria. bioscirep.org/content/38/1/...

B) Nicotinamide directly involved the production of ATP by increasing NAD levels in cells.

2) Both thiamine and Nicotinamide downregulate the increased expression of the p53 protein. ncbi.nlm.nih.gov/pmc/articl... P53 is suggested to be involved in PD and other neurodegenerative diseases. P53 deletion is protective in acute MPTP animal models

onlinelibrary.wiley.com/doi...

As reported by Dr Costantini and other PD patients in this forum, excess doses of Thiamine may exacerbate existing PD symptoms, the same may be the case with Nicotinamide as the mice study demonstrated. The current human trial with Nicotinamide riboside, a different form of Nicotinamide, will shed some light, but so far an effective safe dose for PD has yet to be established

[KERRINGTON in reply to Greenday]

Thank heaven for people like you

[ConnieD in reply to KERRINGTON]

I’ve been taking just the recommended dose for a few weeks and thought it was helpful, now I’m confused 😐

[ConnieD]

I’m not sure how studies work but wouldn’t they have to have accumulated some positive results even to get a study started?

[Gioc in reply to ConnieD]

hi Connie, just to say IMHO that we suffer from PD, we are not really a us, but more than I + I + I and coined this bad word "They" for others such as governments, the scientific community, doctors and even florists and truckers, but this "They" does not really exist, but they are just people who do a job sometimes coordinate, sometimes not.

[ConnieD in reply to Gioc]

Thank you very much Gio! I’m started to think maybe I should just focus on diet and exercise. I feel like there are such mixed reports on a lot of things, then I read a report about how a lot of supplements aren’t regulated and might be doing more harm than good. Depressing.😞

[Gioc in reply to ConnieD]

Oh yeah, take care of yourself, only you can do it better.

[KERRINGTON in reply to ConnieD]

Yes, but think about all the drugs that are regulated....and still wreaking havoc !

We have to weigh each pro and con, read from respected sources, opinions and make an educated decision on our own behalf.

[ConnieD in reply to KERRINGTON]

Thank you! Your right good advice!😊

[sunvox]

Hey Guys,

Sorry it took so long for me to get to this thread. I'm away at my son's college visiting for Parents Weekend and have simply been a little busy.

Nicotinamide is NOT nicotinamide riboside. One is NAM and the other is NR. They are both B3, but they have 1 critical difference and this topic was discussed before in which I quoted the relevant part of the studies.

NAM and all other forms of B3 EXCEPT NR INHIBIT Sirtuins. In the studies they specifically note that it was the action against Sirtuins that caused the trouble. NR is a Sirtuin ENHANCER NOT AN INHIBITOR. This is the critical difference and why I keep telling people it is NOT the same when you take other less expensive forms of B3.

Also, and this is HUGE: the clinical trial linked in the post has the word Nicotinamide in the title, but the researchers are going to administer 1000 mg of NICOTINAMIDE RIBOSIDE to 200 Parkinson's patients for one year starting in January 2020 to see if it slows progression. They are not testing NAM (nicotinamide) but NR nicotinamide riboside.

I will post again later in the week when I have time to dig up the relevant quotes from the study proving what I am saying about Sirtuin's

Bottom line: The dangers outlined were from NAM NOT NR. Yes, they are both B3, but they are NOT the same in what they do in the body.

Joe

[ConnieD in reply to sunvox]

Thank you for cleaning that up Joe!😊

[ConnieD in reply to ConnieD]

*clearing

[sunvox]

OK found it. Here is the relevant quote from the paper:

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"The toxic effects of nicotinamide’s sirtuin inhibition are associated with exacerbation of behavioural motor based symptoms, the neuropathological progression of the model as detected through MRI, and nigral dopaminergic neurodegeneration. These changes were accompanied by reversal of lactacystin induced histone hypoacetylation resulting in histone hyperacetylation and an upregulation of neuroprotective and neurotrophic factors. Such upregulations however did not translate to neuroprotection, rather exacerbated neurodegeneration suggestive that the histone hyperacetylation observed may have also increased expression of neurotoxic factors not studied here. These findings therefore highlight the importance of target specificity within this class of HDACs and demonstrate the contrasting effects of sirtuin inhibition upon cell survival in this, compared to other animal models of PD."

[sunvox]

And here is the opening summary from the Clinical trial of Niagen NOT nicotinamide but nicotinamide RIBOSIDE :

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Notice the TITLE only says nicotinamide, but the summary says nicotinamide riboside over and over.

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"NOPARK is a double-blinded randomized controlled trial that studies nicotinamide supplementation in early Parkinson's disease.

Parkinson's disease (PD) is a major cause of death and disability and has a worldwide socioeconomic impact. It affects ~2% of the population above the age of 65 years and its prevalence increases dramatically as the population ages. The etiology and molecular pathogenesis underlying PD remain unknown. Recent evidence has implicated an impaired neuronal metabolism due to mitochondrial dysfunction, in particular NAD-deficiency is a key-event in the pathogenesis of PD. We propose that in order to correct this metabolic defect and treat PD, we need to boost neuronal NAD levels. This would improve mitochondrial function and could slow PD progression. Nicotinamide riboside is a precursor NAD vitamin. In this study we will investigate if nicotinamide riboside supplementation will correct NAD deficiency and thereby slow progression of PD symptoms. This study will recruit 200 patients with newly diagnosed PD and randomly assign them in an 1:1 ratio to either nicotinamide riboside or placebo administration for 52 weeks. During this trial the investigators will determine if nicotinamide riboside delays PD disease progression measured by clinical monitoring tools (MDS-UPDRS). Patients receiving nicotinamide riboside supplementation will receive a daily dose of 1000mg for the duration of the trial. This trial will also collect biological material from participants to see if nicotinamide riboside supplementation rectifies NAD deficiency and metabolism deficiencies."

[sunvox]

And here is the earlier discussion:

healthunlocked.com/parkinso...?

[Despe in reply to sunvox]

Sunvox,

Like Jim above, unless we heard from you, I would have my husband continue taking NR. What a relief! Thank you for responding and clearing our confusion, although I kept thinking that nicotinamide is not NR(iboside), so why the confusion?

[sunvox in reply to Despe]

"So why the confusion?"

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That is a loaded question for which I have a long winded opinion of an answer. First, vitamin B3 has already been studied extensively in England for other disorders, and there were actually adverse events from patients who overdosed themselves with injections and got sick. More importantly the studies did not show any benefit. Second, Niagen is patented, and the patent is owned by Chromadex who is fighting Elysium Health in court for patent violations, but to date the primary research into Niagen has been paid for by Chromadex which always makes doctors and researchers suspicious. Third, Niagen is new and many doctors are simply not yet aware of the primary difference regarding Niagen versus other forms of vitamin B3, and more importantly the science behind Sirtuins and their role in neurodegeneration and aging is not without controversy. All in all it makes for a confusing topic even for the doctors and scientists.

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Importantly, I do not believe Niagen is a "cure" by a long shot, but I do believe that it is the second most important supplement that PwP can take to help slow the progression of the disease . . I believe the first most important supplement is mannitol or trehalose, and I also believe the same is true for my illness, SCA1.

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For those interested I have changed my personal list of supplements slightly:

healthunlocked.com/ataxia-u...

[Despe in reply to sunvox]

Joe, thanks for your reply.

I read your supplements' list, and I have a couple of questions. 1) Lithium Orotate by PURE contains NAC (checked it out). Wouldn't be more ideal to have just Lithium Orotate (elemental)? 2) Have you tried different doses of B1? What you take is the optimal dose? Thank you.

[Gioc in reply to sunvox]

hi Joe,

How's it going?

always on point !

good!

ciao

[sunvox in reply to Gioc]

Hi Gio,

Well my wife's business was ruined because her partner turned out to be crook, but then that's life, and it's only money . . . but. . . I have 2 wonderful children attending college (one of whom, my son, is working towards becoming a neurosurgeon), a third child working full time at a job she loves, and I'm married to a loving and beautiful woman so all in all I can't complain. Thanks for asking.

Hope all is well with you. How are your symptoms these days?

Joe

[Gioc in reply to sunvox]

Hi Joe,

I'm sorry for your wife's misadventures, but who doesn't have something similar in his life?

In my life, I have learned from experience that predicting human behavior is a biggest difficult task.

Congratulations for the successes of your sons.

Here the winter is over, but spring has not fully blossomed, I think we will pass once again directly from winter to summer and for my symptoms it is not a good thing. However, my annual neurological picture is quite stable, maybe a little improved, I hope.

I hope there are good expectations for you too.

[Greenday]

As it has already been mentioned, this post mainly relates to Nicotinamide and not to Nicotinamide Riboside which exhibits distinguished properties.

However....

It is suggested that NR when orally administered may be metabolized to Nicotinamide in the gut.

Both Nicotinamide (NAM) and Nicotinamide Riboside (NR) increase Nicotinamide mononucleotide (NMN) which is the precursor of NAD+

NR is metabolized through 2 or more suggested pathways

1) NR -> NMN -> NAD+ nature.com/articles/s42255-...

2) NR -> Nicotinamide (NAM) -> NMN -> NAD+ ncbi.nlm.nih.gov/m/pubmed/2...

3) Other mediated transport process

A recent human study showed that only 50% of the subjects showed increase of NR in the blood. In the rest 50% of subjects, NR was metabolized through other possible pathways.

*An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers*

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

"The current study demonstrates that the apparent oral bioavailability of a 1000 mg dose of NR was highly variable among individuals.

While half of the participants showed a significant increase (≥ 100%) in peak blood NR concentration during the pharmacokinetic portion of the study, the remaining subjects showed no or only modest (≤ +50%) changes in blood NR levels. The explanation for this inter-subject variability in post-dose NR levels is not obvious."

"Oral absorption of NR may rely on an active, mediated transport process that varies in active between individuals.

*** It is also possible that NR is degraded to nicotinamide in the gut; nicotinamide is then absorbed and converted to NMN, which can further be converted to NAD+ or dephosphorylated to NR. ***

If true, the degradation of NR to nicotinamide in the gut, which presumably involves purine nucleoside phosphorylase in mammalian and bacterial cells may be a variable step involved in the oral intake of NR

Hence, investigation into the mechanism(s) of NR absorption and metabolism may afford insights into its variable oral bioavailability."

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Pharmacokinetics of NR in humans and concentration in different body tissues, especially brain tissues, are not well examined and understood and studies with larger samples are underway. Also what it may work in certain neurodegenerative diseases may not directly apply to PD as other gene, protein, mutations may be involved.

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Note. A recent study suggest that NR can be metabolized in NMN in the gut by a newly identified NMN transporter nature.com/articles/s42255-...

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Regarding Nicotinamide, some studies suggest that excess levels Nicotinamide may have negative implications in PD.

Human studies show that PD patients exhibit high leves of Nicotinamide N-methyltransferase (NNMT) activity. ncbi.nlm.nih.gov/pubmed/111... ncbi.nlm.nih.gov/pubmed/127... This protein causes the increase conversion of Nicotinamide to produce toxins similar in structure to the ones that induce Parkinson's. This may not be the case in other neurodegenerative disease where the pathologies differ and NNMT is not upregulated.

[Gioc in reply to Greenday]

It seems to me that the b3 NA does not have the same quantitative characteristics as the other two as a precursor to NAM, or NMN, but I could be wrong.