pattismith
Senior Member
- Messages
- 3,946
Targeting sirtuin activity with nicotinamide riboside reduces neuroinflammation in a GWI mouse model
UtsavJoshiabcJames E.EvansacAndrewPearsonabcNicoleSaltielacAdamCseresznyeacTeresaDarceyacJosephOjoacAndrew P.KeeganacSarahOberlinaBenoitMouzonabcDanielParisabcNancyKlimasdKimberlySullivaneMichaelMullanabFionaCrawfordabcLailaAbdullahab
caRoskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, United StatesbOpen University, Milton Keynes, United KingdomcJames A. Haley Veterans' Hospital, Tampa, Florida, United StatesdNova Southeastern University, Fort Lauderdale, United StateseDepartment of Environmental Health, Boston University School of Public Health, Boston, Massachusetts, United States
Highlights
•
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.
•
Consistent with human GWI, blood NAD and Sirt1 are low in our mouse model of GWI.
•
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.
•
Targeting sirtuin activity with NR may represent a new avenue for treating GWI.
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.
@Pyrrhus
UtsavJoshiabcJames E.EvansacAndrewPearsonabcNicoleSaltielacAdamCseresznyeacTeresaDarceyacJosephOjoacAndrew P.KeeganacSarahOberlinaBenoitMouzonabcDanielParisabcNancyKlimasdKimberlySullivaneMichaelMullanabFionaCrawfordabcLailaAbdullahab
caRoskamp Institute, 2040 Whitfield Ave, Sarasota, FL, 34243, United StatesbOpen University, Milton Keynes, United KingdomcJames A. Haley Veterans' Hospital, Tampa, Florida, United StatesdNova Southeastern University, Fort Lauderdale, United StateseDepartment of Environmental Health, Boston University School of Public Health, Boston, Massachusetts, United States
Highlights
•
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.
•
Consistent with human GWI, blood NAD and Sirt1 are low in our mouse model of GWI.
•
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.
•
Targeting sirtuin activity with NR may represent a new avenue for treating GWI.
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.
@Pyrrhus