The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone, ameliorates neurofunctional and neuroinflammatory abnormalities in a rat model of Gulf War Illness.
Animals
Anxiety
/ metabolism
Astrocytes
/ metabolism
Brain
/ metabolism
Cognition
/ physiology
Disease Models, Animal
Female
Hippocampus
/ metabolism
Lipopolysaccharides
/ pharmacology
Male
PPAR gamma
/ agonists
Persian Gulf Syndrome
/ drug therapy
Pyridostigmine Bromide
/ adverse effects
Rats
Rats, Wistar
Rosiglitazone
/ metabolism
Stress, Psychological
/ physiopathology
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
09
09
2020
accepted:
03
11
2020
entrez:
13
11
2020
pubmed:
14
11
2020
medline:
5
1
2021
Statut:
epublish
Résumé
Gulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment, anxiety and depression. We studied a novel model of GWI based on 3 known common GW exposures (GWE): (i) intranasal lipopolysaccharide, to which personnel were exposed during desert sand storms; (ii) pyridostigmine bromide, used as prophylaxis against chemical warfare; and (iii) chronic unpredictable stress, an inescapable element of war. We used this model to evaluate prophylactic treatment with the PPARγ agonist, rosiglitazone (ROSI). Rats were subjected to the three GWE for 33 days. In series 1 and 2, male and female GWE-rats were compared to naïve rats. In series 3, male rats with GWE were randomly assigned to prophylactic treatment with ROSI (GWE-ROSI) or vehicle. After the 33-day exposures, three neurofunctional domains were evaluated: cognition (novel object recognition), anxiety-like behaviors (elevated plus maze, open field) and depression-like behaviors (coat state, sucrose preference, splash test, tail suspension and forced swim). Brains were analyzed for astrocytic and microglial activation and neuroinflammation (GFAP, Iba1, tumor necrosis factor and translocator protein). Neurofunctional data from rats with similar exposures were pooled into 3 groups: naïve, GWE and GWE-ROSI. Compared to naïve rats, GWE-rats showed significant abnormalities in the three neurofunctional domains, along with significant neuroinflammation in amygdala and hippocampus. There were no differences between males and females with GWE. GWE-ROSI rats showed significant attenuation of neuroinflammation and of some of the neurofunctional abnormalities. This novel GWI model recapitulates critical neurofunctional abnormalities reported by Veterans with GWI. Concurrent prophylactic treatment with ROSI was beneficial in this model.
Sections du résumé
BACKGROUND
Gulf War (GW) Illness (GWI) is a debilitating condition with a complex constellation of immune, endocrine and neurological symptoms, including cognitive impairment, anxiety and depression. We studied a novel model of GWI based on 3 known common GW exposures (GWE): (i) intranasal lipopolysaccharide, to which personnel were exposed during desert sand storms; (ii) pyridostigmine bromide, used as prophylaxis against chemical warfare; and (iii) chronic unpredictable stress, an inescapable element of war. We used this model to evaluate prophylactic treatment with the PPARγ agonist, rosiglitazone (ROSI).
METHODS
Rats were subjected to the three GWE for 33 days. In series 1 and 2, male and female GWE-rats were compared to naïve rats. In series 3, male rats with GWE were randomly assigned to prophylactic treatment with ROSI (GWE-ROSI) or vehicle. After the 33-day exposures, three neurofunctional domains were evaluated: cognition (novel object recognition), anxiety-like behaviors (elevated plus maze, open field) and depression-like behaviors (coat state, sucrose preference, splash test, tail suspension and forced swim). Brains were analyzed for astrocytic and microglial activation and neuroinflammation (GFAP, Iba1, tumor necrosis factor and translocator protein). Neurofunctional data from rats with similar exposures were pooled into 3 groups: naïve, GWE and GWE-ROSI.
RESULTS
Compared to naïve rats, GWE-rats showed significant abnormalities in the three neurofunctional domains, along with significant neuroinflammation in amygdala and hippocampus. There were no differences between males and females with GWE. GWE-ROSI rats showed significant attenuation of neuroinflammation and of some of the neurofunctional abnormalities.
CONCLUSION
This novel GWI model recapitulates critical neurofunctional abnormalities reported by Veterans with GWI. Concurrent prophylactic treatment with ROSI was beneficial in this model.
Identifiants
pubmed: 33186383
doi: 10.1371/journal.pone.0242427
pii: PONE-D-20-28392
pmc: PMC7665704
doi:
Substances chimiques
Lipopolysaccharides
0
PPAR gamma
0
Rosiglitazone
05V02F2KDG
Pyridostigmine Bromide
KVI301NA53
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0242427Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL082517
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS060801
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS102589
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS105633
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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