15 replies to this topic

[Supierce]

The therapeutic role of NAD+ modulation in fatty liver disease

https://infoscience....h/record/229863

 

The role of nicotinamide riboside kinases in mammalian NAD+ metabolism

https://infoscience....h/record/229935

 

Hepatic NAD~+ deficiency as a therapeutic target for NAFLD in aging

http://www.cnki.com....BS201610142.htm

[Evan Yang]

There is no doubt NR is a miracle drug on mice. We just need more clinical studies on humans to validate it. 

[Harkijn]

Was this study discussed yet? A quick search on the lead author's name yields no result.

 

The abstract:

NAD⁺ depletion is a common phenomenon in neurodegenerative pathologies. Excitotoxicity occurs in multiple neurologic disorders and NAD⁺ was shown to prevent neuronal degeneration in this process through mechanisms that remained to be determined. The activity of nicotinamide riboside (NR) in neuroprotective models and the recent description of extracellular conversion of NAD⁺ to NR prompted us to probe the effects of NAD⁺ and NR in protection against excitotoxicity. Here, we show that intracortical administration of NR but not NAD⁺reduces brain damage induced by NMDA injection. Using cortical neurons, we found that provision of extracellular NR delays NMDA-induced axonal degeneration (AxD) much more strongly than extracellular NAD⁺. Moreover, the stronger effect of NR compared to NAD⁺ depends of axonal stress since in AxD induced by pharmacological inhibition of nicotinamide salvage, both NAD⁺ and NR prevent neuronal death and AxD in a manner that depends on internalization of NR. Taken together, our findings demonstrate that NR is a better neuroprotective agent than NAD⁺ in excitotoxicity-induced AxD and that axonal protection involves defending intracellular NAD⁺ homeostasis.—Vaur, P., Brugg, B., Mericskay, M., Li, Z., Schmidt, M. S., Vivien, D., Orset, C., Jacotot, E., Brenner, C., Duplus, E. Nicotinamide riboside, a form of vitamin B₃, protects against excitotoxicity-induced axonal degeneration.

 

 

http://www.fasebj.or...0221RR.abstract

 

If anyone can find the full article I would be very interested to read it.

[APBT]

FULL TEXT:

 

Attached Files

•  Nicotinamide riboside, a form of vitamin B3, protects against excitotoxicity-induced axonal degeneration.pdf   1.98MB   20 downloads

[Harkijn]

Thanks APBT!

Excitotoxicity-induced axonal degeneration  may not sound familiar to most of us but just look it up in Wikipedia: all of us have it and we don't want it  .

 

I hope more savvy posters comment on this research.

A few interesting points:

One of the contributors is Dr. Charles Brenner.  

The researchers compared NMN (bought from Millipore-Sigma) with NAD+ and NR (from Chromadex).

They found both NMN and NR protective against axonal degeneration, but NR clearly more so.

Edited by Harkijn, 27 August 2017 - 03:21 PM.

[Evan Yang]

Excitotoxicity has been implicated as a key pathogenic pathway in a number of neurodegenerative diseases and conditions including Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, brain trauma, and stroke

 

https://link.springe...4614-5836-4_145

 

 

Excitotoxicity may be involved in spinal cord injury, stroke, traumatic brain injury, hearing loss(through noise overexposure or ototoxicity), and in neurodegenerative diseases of the central nervous system (CNS) such as multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, alcoholism or alcohol withdrawal and especially over-rapid benzodiazepine withdrawal, and also Huntington's disease.^[3][4] Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia.

 

https://en.wikipedia.../Excitotoxicity

[Michael]

First: this thread appears to be (or be becoming) a grab-bag of different studies on different subjects, similar to the old [Curated] thread that was cut off because it had become unwieldy. May I suggest that folks start new threads on new studies of note, or include them in threads on closely-related subjects?
 

Excitotoxicity-induced axonal degeneration  may not sound familiar to most of us but just look it up in Wikipedia: all of us have it and we don't want it  .

Indeed. However, this kind of acute insult model may not be very useful for modeling the kinds of excitotoxicity to which the "normally" aging brain is subject.
 

They found both NMN and NR protective against axonal degeneration, but NR clearly more so.

Yes — but they only tested it in vitro, which isn't a convincing way to show a meaningful advantage.  There's evidence that little or no NR is actually transported in the blood beyond the liver after oral administration: no one has yet detected it in the plasma beyond the hepatic loop (though that may just be because it's difficult to assay in the complex environment of serum/plasma), and a couple of studies have reported evidence that seems to suggest that it's actually converted to NAM after undergoing liver metabolism. So real in vivo neurons may only be exposed to NAM, NA, or NMN (or NR derived from extracellular NMN, which has been detected in vivo after oral administration).
 
In  that context, note: "cotreatment of cortical neurons with [excitotoxic neurotransmitter] NMDA 100 mM and NAM 5 mM for 24 h demonstrated that NAM is unable to prevent NMDA-induced AxD [axonal degeneration]."

 

It's also worth noting that in different models of axonal degeneration, NAD+ and NMN can be either beneficial or deleterious, depending on the system: see here and here, eg.

Buried in the text, they provide additional evidence in support of the contention that NMN does indeed have to be converted to NR for cellular uptake:
 

NAD+ can be converted extracellularly to NMN by ENPPase and then to NR by 59-ENTase (Fig. 5A). We asked whether extracellular conversion of NAD+ to NR is necessary for NAD+- mediated axonal protection or if this effect is independent of NR action. For this purpose, we probed 59-ENTase activity in cortical neurons, using a high concentration of CMP, a competitive inhibitor of this enzyme (29). First, we treated cortical neurons with 100 mM NMDA, with or without 5 mM NMN for 24 h. Extracellular NMN significantly reduced NMDA-induced AxD and 25 mM CMP reversed the protective effect of NMN (Fig. 5B). Consistent with data in other tissues (28, 30), these data indicate that NMN must be converted to NR to mediate axonal protection.
 
The beneficial effect of NMN was also prevented when cortical neurons were cotreated with NMDA and the ENT1/2 inhibitor DP, confirming that NMN is converted to the nucleoside NR before plasma membrane transport to prevent NMDA-induced AxD. [NMN is a nucleotide; NR is a nucleoside, and uses ENT1/2 (the equilibrative nucleoside transporter) to cross the plasma membrane]. Consistent with a dependence on conversion to NR, NR was more protective at a lower concentration than NMN. Surprisingly, 5 mM NAD+ was slightly but significantly protective, yet neither CMP nor DP blocked the axonal protection conferred by this high concentration of NAD+ (Fig. 5C).

Edited by Michael, 29 August 2017 - 02:17 PM.

[Harkijn]

Thanks, Michael. 

They also claim in vivo results:

Considering the different neuroprotective activities of NAD+ and NR in our in vitro model of excitotoxicity, we asked if NAD+ and NR could be neuroprotective in an in vivo setting of excitotoxicity. For this purpose, we coinjected NMDA (5 nmol) and NAD+ or NR (50 nmol each) into mouse cortical structures as published (40). Strikingly, the volume of the NMDA-induced lesion as measured by MRI was significantly reduced after NR coinjection, whereas NAD+ did not reveal a significant protection (Fig. 2E, F). Thus, NR has a more potent neuroprotective effect than NAD+ in NMDA-induced neurodegeneration, both in vitro and in vivo.

In their conclusion they even see potential for NR testing in Alzheimer's.

[Evan Yang]

prevention is the key dealing with age related diseases. So to validate the prevention effects in mice models in humans could take 5 to 10 years or more. 

Curing Alzheimer's completely may not be possible. My father has Alzheimer's. He has been taking Niagen 250mg for one year.

There is improvement. But not a complete reversal. 

[ceridwen]

Try the Bredesen Protocol. Try taking sulphur as well. Don't give up
Sulphur in the form of MSM that is. Good luck

[ceridwen]

I thought NMN was more effective with Alzheimer's anyway?

[Harkijn]

By mentioning dr.Brenner's conclusion about perspectives for  tests I did not mean to unleash any pain/hope/fear about AD. This is, as Michael points out,  mainly an in vitro study and the in vivo part is about injecting NAD+ and NR in mice. So AD prevention or treatment is really a long way off.

   For the short term it is very interesting that they confirm that NMN needs to change into NR in order to be effective. Of course a real confirmation would be that another lab replicated these results!

   Also: the amounts of NR used by the researchers are very low indeed (admittedly: by injections). Makes me hypothesize that a low dosage of supplementation might be sufficient for general purposes.

   Lastly: I find the positive note on NR encouraging. I think dr.Brenner would have opted for a much more reticent conclusion if the non-publicized studies  had shown negative results.

Edited by Harkijn, 28 August 2017 - 03:07 PM.

[Michael]

Thanks, Michael. 
They also claim in vivo results:
[...]we asked if NAD+ and NR could be neuroprotective in an in vivo setting of excitotoxicity. For this purpose, we coinjected NMDA (5 nmol) and NAD+ or NR (50 nmol each) into mouse cortical structures as published (40). Strikingly, the volume of the NMDA-induced lesion as measured by MRI was significantly reduced after NR coinjection, whereas NAD+ did not reveal a significant protection (Fig. 2E, F). Thus, NR has a more potent neuroprotective effect than NAD+ in NMDA-induced neurodegeneration, both in vitro and in vivo.

Right, but (a) they injected it directly into the brain, which side-steps all the issues around what exactly will be present in the brain after oral NR administration, and (b) they didn't test even injected NMN, which also means the question of relative efficacy for supplement users is unaddressed: you'd certainly expect that injected NR vs. NMN would yield similar relative results as they did in cultured neurons — but, again, the question of what happens after oral administration of one compound vs. the other is not thereby addressed. Eg, if indeed NR is always converted into NAM in the liver after oral administration, then only NAM would reach the brain through the circulation, but if (as Imai's long-term NMN study suggests) NMN actually circulates as such after oral administration, then NMN might actually be superior, despite NR's superiority in cultured neurons.
 

In their conclusion they even see potential for NR testing in Alzheimer's.

Note that NAM, NR, and NMN have all shown efficacy in Alzheimer's model mice.

[Harkijn]

Michael said:

you'd certainly expect that injected NR vs. NMN would yield similar relative results as they did in cultured neurons — but, again, the question of what happens after oral administration of one compound vs. the other is not thereby addressed.

From reading the abstract I was also surprised to find any mention of NMN in the article. The comparison was not really NMN vs NR so why not leave NMN out of the equation, important as this comparison may be. Which one is superior to the other? Is that really important? In view of the absorption rates known so far they might both be useful and perhaps even synergistic..

 

Michael said:

Note that NAM, NR, and NMN have all shown efficacy in Alzheimer's model mice. 

Yes, that's true. However , the conclusion speaks of the human oral availablity of NR in connection with AD. Other studies may correctly and encouragingly point to other B3s. This one is concerned with NR.

[able]

Michael said:

 

From reading the abstract I was also surprised to find any mention of NMN in the article. The comparison was not really NMN vs NR so why not leave NMN out of the equation, important as this comparison may be.

 

 

Yes, I was struck by that also.  Is one reason I say they keep trying to find reasons why NR is better.  

 

Almost seems like they are testing both compounds in a variety of disease models, publishing results for NR, and selectively publishing some tidbits on NMN where it might be inferior to NR, but not the whole picture.

 

I guess that is to be expected when there are big bucks at stake, but makes it hard to trust some of their conclusions.

[alexd]

prevention is the key dealing with age related diseases. So to validate the prevention effects in mice models in humans could take 5 to 10 years or more. 

Curing Alzheimer's completely may not be possible. My father has Alzheimer's. He has been taking Niagen 250mg for one year.

There is improvement. But not a complete reversal. 

If you go to sciencedaily.com and look up calcium pyruvate you can find a study done with calcium pyruvate This study was supoorted by the alzheimers assoc. It showed a marked increase in positive behaviors of both middle aged mice and middle aged alzheimers mimetic mice. I bought some of this from bulksupplements.com.  I found it really sharpened things up. But two things. Initially I took it everyday but I for twice a week ad that is enough for me. But I do not have alzheimers. I also take it with 500mg choline which seems to have a synergistic affect. I put it in 000 capsules.this stuff tastes bad so you really have to encapsulate it.  I thinBest of luckk it is worth a shot.   https://www.scienced...0316194205.htm