| Comim et al., 2017 [85] |
Sepsis induced by cecal ligation and perforation (CLP) |
Wistar rat (60 days old) |
Open field test (OFT) |
24 h and day 10 |
IDO inhibitor prevented the changes in the mitochondrial respiratory chain enzymatic activity in the hippocampus caused by sepsis; Habituation memory was preserved in the sepsis group receiving IDO inhibitor.
|
| Jiang et al., 2018 [87] |
Laparotomy + bile duct ligation (BDL) |
Male Wistar rats (220–240 g) |
Sucrose preference test,
forced swimming,
marble burying test, and elevated plus maze |
0, 7, 14, 21, and 28 days |
Mice exhibit anxiety behavior, a decline in learning and memory function, and locomotor started from day 7 after surgery and symptoms were attenuated by IDO inhibitor; Elevated expression levels of mRNA pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in the brain 14 days post BDL and day 7 in the serum; Constant elevation of IDO-1 and IDO-2 expression in the hippocampus and cerebral cortex, especially 14 days after BDL; The ratio of KYN/TRP increased and 5-HT/TRP decreased in the hippocampus and cerebral cortex in the BDL surgery group. These changes were reversed by 1DO inhibitor treatment; A high level of quinolinic acid was observed on day 28 post-BDL.
|
| Cathomas et al., 2015 [90] |
Single i.p. CD40 agonist antibody (CD40AB) injection |
Male C57BL/6J mice (10–14-week-old) |
Saccharine consumption,
fear conditioning,
and locomotor activity |
Day 2, 4, 5, 6, 7, 8, and 12 after CD40AB injection |
CD40AB induces behavioral effects; decreased saccharin preference, consumption, and operant responding; without affecting locomotor activity or unconditioned stimulus fear and treadmill running; The behavioral effects were led by increased TNF-α levels in the serum and IFN-γ levels in the serum and brain; Increased pro-inflammatory cytokines were followed by increased kynurenine metabolites (KYN, 3-HK, and QUIN) on days 1–7/8 in the serum and brain; Co-injection with TNF-α blocker, Etanercept blocked CD40AB effects on behavioral and the kynurenine pathway; Oral administration of a selective IDO inhibitor prevented the activation of the kynurenine pathway but did not influence acute or extended sickness behavior.
|
| Gomes et al., 2018 [67] |
Single i.p. LPS 0.33 mg/kg |
Male C57BJ/6J mice (24-month-old) |
Open field test, and
sucrose preference test |
24 h |
Decreased the locomotor activity in the LPS group than in the control; Increase in pro-inflammatory cytokines (IL-1β, TNF-α, and IFN-γ) induced by LPS in the hippocampus, striatum, and prefrontal cortex; Decrease in the brain levels of 5-HT and 5-HIAA induced by LPS; LPS significantly decreases KYNA levels and KYNA/KYN ratio (neuroprotective branch) in brain areas; LPS induced an increase of 3-HK and QA levels (neurotoxic branch).
|
| Agostini et al., 2020 [68] |
Single intravenous LPS 100 μg/kg |
Male and female APPswe/PS1dE9 mice model of Alzheimer’s disease and WT (4.5-month-old) |
Food burrowing, and Y-maze test |
24 h, 48 h, and 96 h |
LPS suppressed food burrowing activity in WT males and females and APP/PS1 females; LPS suppressed exploration of Y-maze in all experimental groups, without altering spatial working memory performance; LPS led to a significant increase in plasma levels of IL-6 in all groups, while TNF-α was significantly elevated only in LPS-treated WT females. Plasma levels of IFN-γ were unaltered. Anti-inflammatory IL-10 was significantly higher in LPS-treated female WT and APP/PS1; Increased hippocampal TRP and end metabolites of the 5-HT and KYN pathways 4 h after LPS injection; Immunohistochemistry revealed that LPS had no effects on microglial density in any hippocampal areas (measured by the percentage area covered by Iba1 positive microglial and the number of microglial cells per mm2).
|
| Gomes et al., 2020 [69] |
Single i.p. LPS 1mg/kg |
Male Wistar rats (3-month-old) |
Locomotor activity,
rotarod test, and forced swimming test |
24 h |
Body weight loss and the decrease in locomotor activity induced by LPS; CUR-LNC modulated the levels of pro-inflammatory and anti-inflammatory cytokines (IL-1β, TNF-α, IL-6, and IL-10) in the hippocampus; Up-regulated in IDO-1 and IDO-2 mRNA expression in the hippocampus.
|
| Tufvesson-Alm et al., 2020 [70] |
Two doses i.p LPS 0.83 mg/kg 16 h apart |
FVB/N and C57BL/6J mice (3–4-month-old) |
Open field test, fear conditioning, and Y-maze
|
24 and 48 h |
Mice treated with repeated administration of LPS showed reduced locomotor activity and increased anxiety-like activity; Repeated LPS in FVB/N mice caused an increase in brain KYNA levels as compared to saline-treated mice; Repeated administration of LPS however, did not cause a deficit in the working memory.
|
| Kang et al., 2011 [71] |
Single i.p. LPS 0.8 mg/kg |
CD-1 mice 10–12-week-old |
Open field test, sucrose preference test, and forced swimming test |
24 h |
Body weight and food intake significantly reduced after the LPS injection; No significant difference in locomotor activity from the OFT after the LPS injection; Mice injected with LPS exhibited reduced sucrose preference tests; Hippocampal mRNA expression proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased 24 h post-LPS administration.
|
| Heisler & O’Connor 2015 [54] |
i.p. LPS 0.5 mg/kg |
C57BL/6J mice 12–16-week-old
(group into wild type, IDO−/−, KMO transgenic mice) |
Novel object recognition (NOR) |
24 to 48 h |
LPS challenge induced deficit in novel object recognition (NOR) in WT mice; IDO−/− mice challenged with LPS were secured from NOR deficit; The glial activity was upregulated as indicated by increased mRNA expression of microglial Iba1 and astrocytic GFAP 24 h post LPS challenge; Increased the expression of the pro-inflammatory cytokines IL-1β and TNF-α and reduction in IL-6 in both WT and IDO−/−; Increased mRNA expression of IDO1 48 h post-LPS challenge for WT, a contrast to IDO−/− mice; Acute administration of peripheral kynurenine attenuated depressive-like behaviors; KMO−/− mice administered with LPS were secured from a deficit in NOR.
|
| Guo et al., 2016 [72] |
Single i.p. LPS 3mg/kg
Vs repeated i.p LPS 500 μg/kg every other day for 2 weeks |
Sprague Dawley rats, 230–280 g |
Sucrose preference test and forced swimming test |
2, 4, 6,8, and 10 h |
Repeated LPS administration was associated with a significant reduction in body weight, decreased sucrose preference test and locomotor activity; A rapid increase in glutamate release in the hippocampus in both acute and repeated LPS challenges; Acute LPS administration raised the hippocampal concentrations of TRP, 5-HT, 5-HIAA, and KYN; Repeated LPS challenge did not affect hippocampal TRP concentration but increased the concentration of KYN and the KYN/TRP ratio; The acute LPS challenge reduced the KYNA concentrations, decreased the 5-HT/TRP ratio, and increased the KYN/TRP ratio.
|
| Murray et al., 2015 [89] |
i.p. Poly I:C (12 mg/kg) ± IL-6 (50 μg/kg) |
Female C57BL6/J mice
(WT And IFNAR1−/−) |
Open field test and food burrowing |
24 h to 96 h |
Poly I:C induced sickness behavior in WT mice (decrease in the number of rears in the open field, weight reduction); Higher plasma kynurenine level and KYN/TRP ratio in WT than IFNAR1-/- mice 24-h post poly I:C challenge; Reduced expression of IDO in IFNAR1−/− mice; KP metabolites were undetected in the hippocampus or frontal cortex 3 h post poly I:C challenge.
|
| Gao et al., 2016 [53] |
Cecal ligation and perforation (CLP) induced animal model of sepsis |
Male C57BL/6 mice |
Open field test and fear conditioning test |
12 h and day 14 |
CLP significantly increased the levels of KYN and KYN/TRP ratio and expression of microglial Iba1 in the hippocampus; CLP increased the expression of pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6 in the hippocampus; Treatment with IDO inhibitor, 1-MT downregulated the increased expression of KYN, KYN/TRP ratio, and IDO activity and downregulated marker of microglial activation induced by CLP; Treatment with IDO inhibitors (1-MT and L-TRP) attenuated CLP-induced cognitive impairment; Treatment with L-KYN induced cognitive deficit in sham mice but did not affect the locomotor activity and anxiety-like activity.
|
| Golia et al., 2019 [73] |
i.p LPS 0.33 and 0.83 mg/kg
|
Male C57BL/6 mice 12–15-week-old |
Not specified |
3 h |
Decreased food intake both in high and low-dose LPS; LPS increased hippocampal expression of inflammatory cytokines (IL-1β), TNF-α, IL-6, and COX-2; Acute treatment with a high and low dose of LPS impaired neural plasticity- increased expression of inflammatory markers; IL-1β, PGE2; The modulation of TDO2 was not affected by LPS.
|
| Gibney et al., 2013 [88] |
i.p. Poly I:C 6mg/kg |
Male Sprague Dawley 250–350 g |
Home cage activity test, saccharin preference, and open field test |
6, 2-, 48, and 72 h |
Significantly reduced body weight at 24 h post poly I:C administration; Reduced locomotor activity and anxiety-like behavior 6 h post poly I:C administration; Increased level of IL-1β, IL-6, TNF-α, and CD11b at 6 h time point in frontal cortex and hippocampus; A significant 70-fold increase in IDO expression in the frontal cortex and a 3.3-fold change in the hippocampus at 6 h post poly I:C administration; Increased in KYN/TRP ratio in the brain at 24, 48 and 72 h post poly I:C administration; KYN level in the hippocampus was significantly higher at 24 and 48 h post poly I:C administration, and back to control levels by 72 h; The concentration of TRP increased in the frontal cortex at 24 and 48 h and 6, 24, and 48 h in the hippocampus after poly I:C injection; No alteration in 5-HT concentration in the frontal cortex and hippocampus.
|
| Kelley et al., 2013 [91] |
i.p. Bacillus Calmette–Guerin (BCG) i.p. 108 CFU/mice |
Adult mice Balb/c 4–6-month-old vs. aged mice 20–24-month-old |
Locomotor activity, sucrose preference test, and tail suspension test |
1, 7, 14 or 21 days |
Aged mice exhibited a persistent reduction in body weight (BW) as compared to adult mice with a transient reduction in BW; Aged mice exhibited sickness behavior (reduced locomotor activity) until day 7 and recovered 2 weeks after infection; Locomotor activity was not affected in adult mice after BCG infection; Longer rearing and anhedonia in aged mice than in adult mice after BCG infection; Aged mice demonstrated an increase in KYN/TRP ratio as compared to the saline group and the levels were significant at 7,14, and 21 days after BCG infection.
|
| Walker et al., 2013 [74] |
LPS i.p 1mg/kg (dose to induced depressive-like behavior)
LPS i.p. 0.83 mg/kg (dose to induce acute sickness response) |
CD-1 (6-week-old)
C57BL/6J (12-week-old) |
Locomotor activity, sucrose preference test, and forced swimming test |
2–28 h |
Significant increase in the brain KYN/TRP ratio in LPS-treated mice compared with control; LPS also significantly induced the elevation of KP metabolites, such as QA; LPS decreased body weight, food consumption, and motor activity (sickness behavior), and the effect was not altered by ketamine; LPS decreased sucrose preference (depressive behavior), which was blocked by ketamine pre-treatment; Increase in the brain IL-6 and IL-1β at 6 and IL-6 at 28-H p.i. and the effects were not altered by ketamine; LPS increased plasma KYN/TRP ratio at 6 and 28 h, and brain KYN/TRP ratio at 28 h after treatment, and the effects were not affected by ketamine treatment.
|
| Zhao et al., 2019 [75] |
i.p LPS 0.5 mg/kg
and/or unpredictable chronic mild stress (UCMS) |
Adult male C57BL/6J mice, 8–12-week-old |
Open field test, forced swimming test, and tail suspension test. |
24 h |
No significant differences in locomotor activity in both LPS and UCMS mice; LPS induced more apparent depressive-like behaviors than UCMS; LPS induced robust expression of TNF-α, IL-1β, and IL-6 in the serum and brain areas (prefrontal cortex, hippocampus, and striatum), as compared to UCMS mice; IDO expression in the brain (prefrontal cortex and hippocampus) was significantly increased following LPS and UCMS; The decrease of 5-HT and BDNF was detected only in the hippocampus of LPS-stressed mice.
|
| Schneiders et al., 2015 [76] |
i.p LPS 50 or 2500 μg/kg |
C/EBPβ+/+ (Wild type) and C/EBPβ-/- (KO) mice 6–12 weeks old |
Locomotor activity (two-compartment cage) |
8 or 24 h |
LPS stimulation showed drop in locomotor activity in response to normal environmental stress (NES) after 2 h, while the activity of KO mice remained significantly high; The plasma level of IL-6 and IL-10 of both WT and KO increased 8 h p.i. with high dose LPS and returned to basal levels at 24 h in WT mice. (TNF-α was not detected); Higher expression of inflammatory mediators (IL-6, TNF-α, IL-10 in the brains of KO mice) 24 h after LPS stimulation as compared to WT; LPS induced significant upregulation of IDO-mRNA expression in the hypothalamus 8 h p.i in WT which was absent in KO mice; Tryptophan-hydroxylase (TPH) 2 was significantly increased after LPS treatment in KO mice, but not in WT; mRNA expression of IDO and TPH2 in the hypothalamus returned to basal levels at 24 h in both genotypes; The mRNA expression of KMO was unchanged at 8 h and significantly higher at 24-h p.i. in KO mice compared to WT mice; The IDO expression in the liver was significantly higher in KO mice 8 h p.i. compared to WT mice and no difference in both genotypes at 24 h.
|
| Dinel et al., 2014 [77] |
i.p LPS 5ug |
Male db/db and db/+ mice between 10 and 12 weeks |
Two-compartment cage and forced swimming test |
2 h to 25 h |
LPS significantly increased the duration of immobility 24 h post-LPS in db/+; LPS significantly increased the brain KYN/TRP ratio and this increase was significantly reduced in db/db mice; LPS significantly increased plasma levels of IL-1b, TNF-a, and IL-10 in db/+ and db/db mice 2 h after treatment; LPS-treated db/db mice exhibited similar peripheral levels of KYN to their db/+ counterparts but lower brain KYN levels; LPS significantly increased hippocampus mRNA expression of IL-1β, TNF-α, IL-6, IFN-γ, and IL-10 in both db/+ and db/db mice.
|
| Lu et al., 2021 [78] |
i.p LPS 1.0 mg/kg |
Male C57BL/6J mice, 4–5 weeks of age |
Sucrose preference test, forced swimming test, and tail suspension test |
24 h |
LPS-induced depression-like behavior; Mice administered with LPS demonstrated the elevation of the TNF-α, IL-6, IL-1β, IL-10, TRP, and KYN levels and lower 5-HT in the hippocampus.
|
| Farzi et al., 2015 [79] |
i.p. LPS (0.1 or
0.83 mg/kg) |
Male C57BL/6N mice, aged at 10 weeks |
Sucrose preference test, open field test, forced swimming test, and tail suspension test |
21 h |
Aggravation of sickness behavior induced by FK565 (NOD1 agonist) or MDP (NOD2 agonist) in combination with LPS; The sickness behavior was paralleled by enhanced plasma and cerebral mRNA levels of proinflammatory cytokines (IFN-c, IL-1b, IL-6, TNF-a), as well as enhanced plasma levels of kynurenine.
|
| Zhang et al., 2018 [80] |
i.p. LPS (0.5 mg/kg)
and/or unpredictable chronic mild stress (UCMS) |
Cat C overexpression (CAT C OE) and Cat C knockdown (CAT C KD) transgenic mice together with wild type (WT) at 8-weeks-old |
Open field test, forced swimming test, and tail suspension test |
24 h |
Marked increase in IDO levels in the hippocampus and prefrontal cortex of LPS and UCMS mice; Cat C OE induced peripheral and central inflammatory response (promoted microglia/macrophage activation) with significantly increased TNFα, IL-1β and IL-6 in serum, hippocampus, and prefrontal cortex; Cat C OE promoted upregulation of IDO and downregulation of 5HT expression in the brain, and subsequently aggravated depression-like behaviors.
|
| Carabelli et al., 2020 [81] |
i.p. LPS 250μg/kg |
Male Wistar rats, 60 days-old |
Open field test and forced swimming test |
24 h |
LPS led to a marked weight loss; LPS induced a depressive-like behavior, and the symptoms were blocked by 1-methyltryptophan (IDO inhibitor); LPS increased 5HIAA/5HT and IDO and decreased 5-HT levels in the hippocampus.
|
| Peyton et al., 2019 [82] |
i.p. 2X LPS (0.25 mg/kg, 0.50mg/kg, or saline) 16 h apart |
Male C57Bl/6J mice, three months old |
Pavlovian conditioning, accelerated rotarod radial 8-arm maze, and prepulse inhibition |
24 h, 48 h, and 144 h |
Mice treated with peripheral low-dose LPS (0.25 mg/kg) exhibited significant increases in pre-cortex KYN and KYNA; Dual LPS administration did not impair exploratory activity; Dual LPS-treated mice showed deficits in reference memory while working memory was observed to be normal.
|
| Danielski et al., 2018 [86] |
Cecal ligation and perforation (CLP) |
Male Wistar rats, approximately 60 days old, 250–350 g |
Open field test and object recognition test |
24 h-day 10 |
Pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) levels in the hippocampus significantly increased 24 h after sepsis induction; KYN in the cortex, but not in the hippocampus significantly increased 24 h after sepsis induction.
|
| Imbeault et al., 2020 [83] |
Single i.p LPS 0.83mg/kg |
Male C57Bl6/NCrl mice aged 13 to 18 weeks |
Elevated plus maze and fear conditioning test |
24–96 h |
LPS-induced anxiety-like behavior and cognitive deficits; Changes in behavior were accompanied by an increase in brain and plasma KYN: TRP ratio; Pre-treatment with IDO1 inhibitor (1-MT) 7 days before LPS injection reduced the levels of KYN and the KYN: TRP ratio in the brain; Pre-treatment with TDO2 inhibitor (680C91) did not change the levels of KYN and KYN: TRP ratio in the brain and serum, and KYNA levels in the serum; Pre-treatment with IDO1 inhibitor and TDO2 inhibitor failed to reduce anxiety parameters and mitigate cognitive deficit produced by LPS.
|
| Choubey et al., 2019 [84] |
Single i.p. LPS 0.83 mg/kg and/or restraint stress (RS) |
Adult male Swiss albino mice |
Open field test and forced swimming test |
3–24 h |
Acute systemic inflammatory exposure to LPS, RS, and RS plus LPS induced anxiety-like behavior and depression-like behavior; LPS, RS, and RS plus LPS augmented the activation of the TLR-4 receptor that induces the release of pro-inflammatory IL-1β in the hippocampus region; Exposure to RS, LPS, and RS plus LPS significantly upregulated NF-ƙB and IDO-1 gene expression in the hippocampus region.
|
