Targeting sirtuin activity with nicotinamide riboside reduces neuroinflammation in a GWI mouse model, 2020, Joshi et al

Dolphin · Apr 30, 2020

NeuroToxicology
Available online 25 April 2020

Full Length Article
Targeting sirtuin activity with nicotinamide riboside reduces neuroinflammation in a GWI mouse model
Utsav Joshi abc
James E.Evans ac
Andrew Pearson abc
NicoleSaltielacAdamCseresznyeacTeresaDarceyacJosephOjoacAndrew P.KeeganacSarahOberlinaBenoitMouzonabcDanielParisabcNancyKlimasdKimberlySullivaneMichaelMullanabFionaCrawfordabcLailaAbdullahabc
a
Roskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, United States
b
Open University, Milton Keynes, United Kingdom
c
James A. Haley Veterans' Hospital, Tampa, Florida, United States
d
Nova Southeastern University, Fort Lauderdale, United States
e
Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts, United States
Received 21 February 2020, Revised 26 March 2020, Accepted 20 April 2020, Available online 25 April 2020.

https://doi.org/10.1016/j.neuro.2020.04.006
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Highlights

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Blood NAD and Sirt1 are low in GW veterans with GWI.

•
Treatment with NR increased NAD and alleviated fatigue-like behavior in a mouse model of GWI.

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Consistent with human GWI, blood NAD and Sirt1 are low in our mouse model of GWI.

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Brain NAD levels were normal in GWI mice but are increased in both GWI and control mice after NR treatment.

•
Treatment with NR increased Sirt1 activity and reduced neuroinflammation in the brains of GWI mice.

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Targeting sirtuin activity with NR may represent a new avenue for treating GWI.
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Abstract

Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War (GW), who suffer from symptoms that reflect ongoing mitochondria dysfunction.

Brain mitochondria bioenergetics dysfunction in GWI animal models corresponds with astroglia activation and neuroinflammation.

In a pilot study of GW veterans (n = 43), we observed that blood nicotinamide adenine dinucleotide (NAD) and sirtuin 1 (Sirt1) protein levels were decreased in the blood of veterans with GWI compared to healthy GW veterans.

Since nicotinamide riboside (NR)-mediated targeting of Sirt1 is shown to improve mitochondria function, we tested whether NR can restore brain bioenergetics and reduce neuroinflammation in a GWI mouse model.

We administered a mouse diet supplemented with NR at 100μg/kg daily for 2-months to GWI and control mice (n = 27).

During treatment, mice were assessed for fatigue-type behavior using the Forced Swim Test (FST), followed by euthanasia for biochemistry and immunohistochemistry analyses.

Fatigue-type behavior was elevated in GWI mice compared to control mice and lower in GWI mice treated with NR compared to untreated GWI mice.

Levels of plasma NAD and brain Sirt1 were low in untreated GWI mice, while GWI mice treated with NR had higher levels, similar to those of control mice.

Deacetylation of the nuclear-factor κB (NFκB) p65 subunit and peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) was an increase in the brains of NR-treated GWI mice.

This corresponded with a decrease in pro-inflammatory cytokines and lipid peroxidation and an increase in markers of mitochondrial bioenergetics in the brains of GWI mice.

These findings suggest that targeting NR mediated Sirt1 activation restores brain bioenergetics and reduces inflammation in GWI mice.

Further evaluation of NR in GWI is warranted to determine its potential efficacy in treating GWI.

Keywords
Gulf war illness
Nicotinamide Riboside(NR)
Neuroinflammation
Nicotinamide Adenine Dinucleotide(NAD)
Sirtuin
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cassava7 · Apr 30, 2020

This is from the team at Roskamp Institute that has a NIH R21 exploratory grant for investigating the "Application of lipidomics to identify biomarkers of immune and mitochondrial disturbances in chronic fatigue syndrome". Nancy Klimas is a co-principal investigator on the grant. https://projectreporter.nih.gov/project_info_description.cfm?aid=9841376&icde=31258613

From the Wikipedia article on nicotinamide riboside:

Nicotinamide riboside (NR) is claimed to be a new form pyridine-nucleoside of vitamin B3 that functions as a precursor to nicotinamide adenine dinucleotide or NAD+.[1][2]
[...]
Although it is a form of vitamin B3, NR exhibits unique properties that distinguish it from the other B3 vitamins—niacin and nicotinamide. In a head-to-head experiment conducted on mice, each of these vitamins exhibited unique effects on the hepatic NAD+ metabolome with unique kinetics, and with NR as the form of B3 that produced the greatest increase in NAD+ at a single timepoint.[16]
[...]
Despite being an NAD+ precursor, nicotinamide acts as an inhibitor of the NAD+-consuming sirtuin enzymes.[10] When sirtuins consume NAD+, they create nicotinamide and O-acetyl-ADP-ribose as products of the deacetylation reaction. Consistent with high-dose nicotinamide as a sirtuin inhibitor, NR and niacin, but not nicotinamide, have been shown to increase hepatic levels of O-acetyl-ADP-ribose.[16]
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Cinders66 · May 1, 2020

I took Nadh many years ago when there was a lot of hype, no benefits, I read elsewhere this week about b3 benefitting something else potentially m.e related, I forget now.
Is anyone supplementing along these lines getting any benefit ? For me i would like to try things that can reduce neuro inflammation/ microglial activity.

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