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Dihydronicotinamide riboside is a potent NAD+ concentration enhancer in vitro and in vivo

dihydronicotinamide riboside nrh nad+ precursor

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#1 Fredrik

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Posted 04 April 2019 - 09:31 PM


Attached File  Screenshot 2019-04-05 at 00.02.41.png   219.3KB   0 downloadsPublished in Journal Of Biological Chemistry today Thursday 4 April.

 

"NR and NMN require large dosages for effect. Herein we describe synthesis of dihydronicotinamide riboside (NRH) and the discovery that NRH is a potent NAD+ concentration enhancing agent, which acts within as little as 1 hr after administration to mammalian cells to increase NAD+ concentrations by 2.5-10 fold over control values.

 

Comparisons to NR and NMN show that in every instance NRH provides greater NAD+ increases at equivalent concentrations. NRH also provides substantial NAD+ increases in tissues when administered by intraperitoneal injection to  C57BL/6J mice.

 

NRH substantially increases NAD+/NADH ratio in cultured cells and in liver, and no induction of apoptotic markers or significant increases in lactate levels in cells. Cells treated with NRH are resistant to cell death caused by NAD+-depleting genotoxins such as hydrogen peroxide and methylmethane sulfonate. 

 

Studies to identify its biochemical mechanism of action showed that it does not inhibit NAD+ consumption suggesting it acts as a biochemical precursor to NAD+. Cell lysates possess an ATP-dependent kinase activity which efficiently converts NRH to the compound NMNH, but independent of Nrk1 or Nrk2.

 

These studies identify a putative new metabolic pathway to NAD+, and a potent pharmacologic agent for NAD+ concentration enhancement in cells and tissues."

 

http://www.jbc.org/c...c.RA118.005772.

 

http://www.jbc.org/c...pKdKMwhukJg2cuA

 

Attached File  Screenshot 2019-04-05 at 00.03.02.png   370.56KB   0 downloads


Edited by Fredrik, 04 April 2019 - 09:50 PM.

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#2 Phoebus

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Posted 04 April 2019 - 11:36 PM

Ah! 

 

So now the alternative to NR/NMN are starting to show up. Nice. I like it. Hopefully this gets to human trials right quickly and hits the market soon. 



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#3 tunt01

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Posted 05 April 2019 - 12:20 AM

FYI.  They checked the mice 4 hours after administration of NRH.  Pretty significant levels.



#4 ledgf

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Posted 05 April 2019 - 01:05 PM

Shown to be far more powerful in cell culture:
 

http://www.jbc.org/c...005772.full.pdf


Just to keep MikeinDC from having a heart attack, the patent is assigned to Chromadex:

https://patents.goog...oq=US10183036B2


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#5 Fredrik

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Posted 05 April 2019 - 08:57 PM

Dr Charles Brenner of Chromadex comments on NRH:

 

Attached File  Screenshot 2019-04-05 at 23.10.14.png   137.51KB   7 downloads


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#6 Phoebus

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Posted 05 April 2019 - 10:15 PM

Dr Charles Brenner of Chromadex comments on NRH:

 

attachicon.gif Screenshot 2019-04-05 at 23.10.14.png

 

novel kinase? Acid labile? what does this mean? 


Edited by Phoebus, 05 April 2019 - 10:16 PM.


#7 tunt01

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Posted 06 April 2019 - 12:40 AM

novel kinase? Acid labile? what does this mean? 

 

acid labile = will be broken down in the stomach and can't be orally administered

 

novel kinase = novel enzyme that attaches a phosphate group to it (participates in cell entry).  basically he's saying it can get into cells through its own unique method outside of the NRK pathway that NR uses


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#8 Reven

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Posted 06 April 2019 - 02:22 PM

Abstract

Interest in pharmacological agents capable of increasing cellular NAD+ concentrations has stimulated investigations of nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). NR and NMN require large dosages for effect. Herein we describe synthesis of dihydronicotinamide riboside (NRH) and the discovery that NRH is a potent NAD+ concentration enhancing agent, which acts within as little as 1 hr after administration to mammalian cells to increase NAD+ concentrations by 2.5-10 fold over control values. Comparisons to NR and NMN show that in every instance NRH provides greater NAD+ increases at equivalent concentrations. NRH also provides substantial NAD+ increases in tissues when administered by intraperitoneal injection to  C57BL/6J mice. NRH substantially increases NAD+/NADH ratio in cultured cells and in liver, and no induction of apoptotic markers or significant increases in lactate levels in cells. Cells treated with NRH are resistant to cell death caused by NAD+-depleting genotoxins such as hydrogen peroxide and methylmethane sulfonate. Studies to identify its biochemical mechanism of action showed that it does not inhibit NAD+ consumption suggesting it acts as a biochemical precursor to NAD+. Cell lysates possess an ATP-dependent kinase activity which efficiently converts NRH to the compound NMNH, but independent of Nrk1 or Nrk2. These studies identify a putative new metabolic pathway to NAD+, and a potent pharmacologic agent for NAD+ concentration enhancement in cells and tissues.

 

http://m.jbc.org/con...bc.RA118.005772

 


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#9 stefan_001

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Posted 06 April 2019 - 05:27 PM

The results are impressive. This may be interesting for sublingual use. But probably requires new approvals or then end up in the unregulated NMN supplements.


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#10 Chrys

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Posted 06 April 2019 - 08:20 PM

This is great news; however, what caught my eye was the statement "Cells treated with NRH are resistant to cell death caused by NAD+-depleting genotoxins such as hydrogen peroxide and methylmethane sulfonate."

 

In another study hydrogen peroxide was found to lessen or abate homeostasis of the positive effects of NMN. I was about to begin H2O2.

 

 

 

 


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#11 JamesPaul

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Posted 06 April 2019 - 09:01 PM

Could NRH be enterically coated and escape degradation in the stomach, and be absorbed in the small intestine?


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#12 Fredrik

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Posted 07 April 2019 - 05:23 AM

This is great news; however, what caught my eye was the statement "Cells treated with NRH are resistant to cell death caused by NAD+-depleting genotoxins such as hydrogen peroxide and methylmethane sulfonate."

In another study hydrogen peroxide was found to lessen or abate homeostasis of the positive effects of NMN. I was about to begin H2O2.


Where is the HUMAN data showing health benefits of drinking hydrogen peroxide when taking NR/NMN?

I am not touching that stuff.

Edited by Fredrik, 07 April 2019 - 05:26 AM.

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#13 Joe Garma

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Posted 08 April 2019 - 03:18 AM

Does anyone know if there are plans to offer Dihydronicotinamide riboside as a supplement?

 

Both NMN and NR became available to the public prior to human testing.

 


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#14 orion22

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Posted 08 April 2019 - 07:39 AM

Synthesis of dihydronicotinamide riboside “NRH” (1-((2R,3S,4R,5R)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-1,4- dihydropyridine-3-carboxamide). In a flame dried flask under an Argon atmosphere, Nicotinamide riboside (NR) (100mg, 0.24 mmol) was added to 10 ml of 50 m M potassium phosphate pH = 8.5 at 0 oC. After 5 minutes, 0.8 eq of sodium dithionate (Na2S2O4) was added and then run reaction at 0 oC for 30 minutes. (Progress of the reaction was by guest on April 8, 2019 http://www.jbc.org/ Downloaded from NRH increases NAD+ concentrations in cells and tissues 9 monitored by HPLC: 70% of starting material was consumed after 30 minutes). The crude product was purified by C-18 column using water as eluent to obtain light yellow solid (2). Yield 70%.

is this hard to make  any chemist here who knows?







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