scholarly journals Nafamostat reduces systemic inflammation in TLR7-mediated virus-like illness

2022 ◽  
Vol 19 (1) ◽  
Author(s):  
Abi G. Yates ◽  
Caroline M. Weglinski ◽  
Yuxin Ying ◽  
Isobel K. Dunstan ◽  
Tatyana Strekalova ◽  
...  
Keyword(s):  
Virus Infection ◽  
Inflammatory Response ◽  
Forced Swim Test ◽  
Preference Test ◽  
Blood Analysis ◽  
Sickness Behaviour ◽  
Ssrna Virus ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Sucrose Preference Test

Abstract Background The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to an ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model. Methods CD-1 mice received an intraperitoneal injection of R848 (200 μg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100 μL, 3 mg/kg in 5% dextrose) or 5% dextrose alone. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 h post-challenge to measure markers of peripheral and central inflammation by blood analysis, immunohistochemistry and qPCR. Results R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment. Conclusions Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.

scholarly journals Nafamostat reduces systemic inflammation in TLR7-mediated virus-like illness

2021 ◽  
Author(s):  
Abi G. Yates ◽  
Caroline M. Weglinski ◽  
Yuxin Ying ◽  
Tatyana Strekalova ◽  
Daniel C. Anthony
Keyword(s):  
Virus Infection ◽  
Inflammatory Response ◽  
Forced Swim Test ◽  
Preference Test ◽  
Blood Analysis ◽  
Sickness Behaviour ◽  
Ssrna Virus ◽  
Ifn Γ ◽  
Anti Inflammatory ◽  
Sucrose Preference Test

Abstract Background: The serine protease inhibitor nafamostat has been proposed as a treatment for COVID-19, by inhibiting TMPRSS2-mediated viral cell entry. Nafamostat has been shown to have other, immunomodulatory effects, which may be beneficial for treatment, however animal models of ssRNA virus infection are lacking. In this study, we examined the potential of the dual TLR7/8 agonist R848 to mimic the host response to a ssRNA virus infection and the associated behavioural response. In addition, we evaluated the anti-inflammatory effects of nafamostat in this model. Methods: CD-1 mice received an intraperitoneal injection of R848 (200μg, prepared in DMSO, diluted 1:10 in saline) or diluted DMSO alone, and an intravenous injection of either nafamostat (100μL, 3mg/kg in saline) or saline. Sickness behaviour was determined by temperature, food intake, sucrose preference test, open field and forced swim test. Blood and fresh liver, lung and brain were collected 6 hours post-challenge to measure markers of peripheral and central inflammation by blood analysis and qPCR. Results: R848 induced a robust inflammatory response, as evidenced by increased expression of TNF, IFN-γ, CXCL1 and CXCL10 in the liver, lung and brain, as well as a sickness behaviour phenotype. Exogenous administration of nafamostat suppressed the hepatic inflammatory response, significantly reducing TNF and IFN-γ expression, but had no effect on lung or brain cytokine production. R848 administration depleted circulating leukocytes, which was restored by nafamostat treatment. Conclusions: Our data indicate that R848 administration provides a useful model of ssRNA virus infection, which induces inflammation in the periphery and CNS, and virus infection-like illness. In turn, we show that nafamostat has a systemic anti-inflammatory effect, in the presence of the TLR7/8 agonist. Therefore, the results indicate that nafamostat has anti-inflammatory actions, beyond its ability to inhibit TMPRSS2, that might potentiate its anti-viral actions in pathologies such as COVID-19.

13. FGF2 Gene is required for Antidepressant Treatment Effects

2018 ◽  
Author(s):  
Jessica MacGregor
Keyword(s):  
Open Field ◽  
Antidepressant Treatment ◽  
Forced Swim Test ◽  
Antidepressant Drugs ◽  
Preference Test ◽  
Antidepressant Effect ◽  
Plus Maze ◽  
Brain Changes ◽  
Carry Over ◽  
Sucrose Preference Test

gene in humans have been shown to predict non-responsiveness to antidepressant drugs; suggesting that FGF2 is required for antidepressants to work. In this study, we hypothesized that antidepressants will not work in rodents that lack the FGF2 gene. Hence, we tested antidepressant treatment in transgenic mice that had the FGF2 gene knocked out. Chronic unpredictable stress (CUS) has been used for several decades to produce a reliable depressive and anxious phenotype in mice. This study followed a CUS paradigm and used fluoxetine (Prozac) as antidepressant treatment. Mice received daily fluoxetine administration beginning on week three of CUS and continued until the end of week five to provide an antidepressant effect and reverse the effects of stress. To test for levels of anxiety and depression, a battery of behavioral tests was conducted which began from the least stressful (i.e. sucrose preference test, open field maze, elevated plus maze) to the most stressful test (forced swim test) to prevent testing carry-over effects. AnyMaze software was used to measure behavior in the open field and elevated plus mazes by recording the amount of time each mouse spent in certain parts of the maze. Future studies will examine brain changes associated with FGF2 gene deletion – particularly in astrocyte cells – which might be necessary for successful antidepressant action. Hopefully, this will elucidate novel therapeutic targets for antidepressant and anti-anxiety medication. 

scholarly journals The Flavonoid Isoliquiritigenin Reduces Lung Inflammation and Mouse Morbidity during Influenza Virus Infection

2015 ◽  
Vol 59 (10) ◽  
pp. 6317-6327 ◽  
Author(s):  
Hussein Traboulsi ◽  
Alexandre Cloutier ◽  
Kumaraswamy Boyapelly ◽  
Marc-André Bonin ◽  
Éric Marsault ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Inflammatory Response ◽  
Lung Inflammation ◽  
Inflammatory Cell ◽  
Influenza Virus Infection ◽  
Cytokine Gene Expression ◽  
Cell Recruitment ◽  
Inflammatory Cell Recruitment ◽  
Anti Inflammatory

ABSTRACTThe host response to influenza virus infection is characterized by an acute lung inflammatory response in which intense inflammatory cell recruitment, hypercytokinemia, and a high level of oxidative stress are present. The sum of these events contributes to the virus-induced lung damage that leads to high a level of morbidity and mortality in susceptible infected patients. In this context, we identified compounds that can simultaneously reduce the excessive inflammatory response and the viral replication as a strategy to treat influenza virus infection. We investigated the anti-inflammatory and antiviral potential activities of isoliquiritigenin (ILG). Interestingly, we demonstrated that ILG is a potent inhibitor of influenza virus replication in human bronchial epithelial cells (50% effective concentration [EC50] = 24.7 μM). In addition, our results showed that this molecule inhibits the expression of inflammatory cytokines induced after the infection of cells with influenza virus. We demonstrated that the anti-inflammatory activity of ILG in the context of influenza virus infection is dependent on the activation of the peroxisome proliferator-activated receptor gamma pathway. Interestingly, ILG phosphate (ILG-p)-treated mice displayed decreased lung inflammation as depicted by reduced cytokine gene expression and inflammatory cell recruitment. We also demonstrated that influenza virus-specific CD8+effector T cell recruitment was reduced up to 60% in the lungs of mice treated with ILG-p (10 mg/kg) compared to that in saline-treated mice. Finally, we showed that administration of ILG-p reduced lung viral titers and morbidity of mice infected with the PR8/H1N1 virus.

Targeting Kynurenine Pathway in Olfactory Bulbectomised Mice: Inflammatory and Neurodegerative Pathway of Depression

2017 ◽  
Vol 41 (S1) ◽  
pp. s140-s140 ◽  
Author(s):  
Y. Bansal ◽  
A. Kuhad ◽  
R. Singh ◽  
P. Saroj
Keyword(s):  
Quinolinic Acid ◽  
Forced Swim Test ◽  
Nordihydroguaiaretic Acid ◽  
Preference Test ◽  
Kynurenine Pathway ◽  
Hplc Method ◽  
Simultaneous Estimation ◽  
Post Surgery ◽  
Sucrose Preference Test ◽  
Olfactory Deficit

Aims and objectivesThe aim of study was to evaluate the pharmacotherapeutic efficacy of NDGA in experimental paradigm of depression i.e. olfactory bulbectomy (OB) specifically targeting kynurenine pathway.Materials and methodDepression like behaviours was induced in OB mice and evaluated by assessment of various behavioural (olfactory deficit test, forced swim test, splash test, open field test, sucrose preference test), biochemical (catalase, reduced glutathione, SOD, nitrite, MAO-A, MDA, corticosterone), inflammatory cytokines (TNF- α, IL-1β, IL-6, IFN-γ) levels and alterations in delta sleep was recorded using EEG. Kynurenine pathway metabolites were determined in plasma and brain using HPLC method. After 14 days post-surgery, olfactory bulbectomized (OBX) mice were administered nordihydroguaiaretic acid (5 mg/kg, 10 mg/kg and 25 mg/kg) daily i.p.ResultsWe have developed a new HPLC method for simultaneous estimation of monoamines and kynurenine pathway metabolites in plasma and brain samples of mice. Chronic treatment with nordihydroguaiaretic acid significantly restored all behavioural, biochemical and neurochemical alterations in OBX mice and increase in quinolinic acid and decrease in kynurenic acid point out the neurodegeneration hypothesis of depression.ConclusionNordihydroguaiaretic acid showed potent neuropharmacotherapeutic effect in OBX mice by virtue of its strong anti-oxidant, anti-inflammatory, anti-stress and by restoring quinolinic acid levels.

scholarly journals Intestinal CD103+CD11b− dendritic cells restrain colitis via IFN-γ-induced anti-inflammatory response in epithelial cells

2015 ◽  
Vol 9 (2) ◽  
pp. 336-351 ◽  
Author(s):  
A R B M Muzaki ◽  
P Tetlak ◽  
J Sheng ◽  
S C Loh ◽  
Y A Setiagani ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Ifn Γ ◽  
Anti Inflammatory

scholarly journals A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats

2011 ◽  
Vol 115 (4) ◽  
pp. 812-821 ◽  
Author(s):  
Jing Wang ◽  
Yossef Goffer ◽  
Duo Xu ◽  
David S. Tukey ◽  
D. B. Shamir ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Forced Swim Test ◽  
Preference Test ◽  
Sucrose Preference ◽  
Spared Nerve Injury ◽  
Chronic Neuropathic Pain ◽  
Swim Test ◽  
Forced Swim ◽  
Sucrose Preference Test

Background Chronic pain is associated with depression. In rodents, pain is often assessed by sensory hypersensitivity, which does not sufficiently measure affective responses. Low-dose ketamine has been used to treat both pain and depression, but it is not clear whether ketamine can relieve depression associated with chronic pain and whether this antidepressant effect depends on its antinociceptive properties. Methods The authors examined whether the spared nerve injury model of neuropathic pain induces depressive behavior in rats, using sucrose preference test and forced swim test, and tested whether a subanesthetic dose of ketamine treats spared nerve injury-induced depression. Results Spared nerve injury-treated rats, compared with control rats, showed decreased sucrose preference (0.719 ± 0.068 (mean ± SEM) vs. 0.946 ± 0.010) and enhanced immobility in the forced swim test (107.3 ± 14.6s vs. 56.2 ± 12.5s). Further, sham-operated rats demonstrated depressive behaviors in the acute postoperative period (0.790 ± 0.062 on postoperative day 2). A single subanesthetic dose of ketamine (10 mg/kg) did not alter spared nerve injury-induced hypersensitivity; however, it treated spared nerve injury-associated depression-like behaviors (0.896 ± 0.020 for ketamine vs. 0.663 ± 0.080 for control rats 1 day after administration; 0.858 ± 0.017 for ketamine vs. 0.683 ± 0.077 for control rats 5 days after administration). Conclusions Chronic neuropathic pain leads to depression-like behaviors. The postoperative period also confers vulnerability to depression, possibly due to acute pain. Sucrose preference test and forced swim test may be used to compliment sensory tests for assessment of pain in animal studies. Low-dose ketamine can treat depression-like behaviors induced by chronic neuropathic pain.

scholarly journals Sex-Based Impact of Creatine Supplementation on Depressive Symptoms, Brain Serotonin and SSRI Efficacy in an Animal Model of Treatment-Resistant Depression

2021 ◽  
Vol 22 (15) ◽  
pp. 8195
Author(s):  
Shami Kanekar ◽  
Robert Ettaro ◽  
Michael D. Hoffman ◽  
Hendrik J. Ombach ◽  
Jadeda Brown ◽  
...  
Keyword(s):  
Selective Serotonin Reuptake Inhibitors ◽  
Motor Behavior ◽  
Forced Swim Test ◽  
Creatine Supplementation ◽  
Preference Test ◽  
Brain Serotonin ◽  
Moderate Altitude ◽  
Major Depressive ◽  
Resistant Depression ◽  
Sucrose Preference Test

Background: Rates of major depressive disorder (MDD) increase with living at altitude. In our model, rats housed at moderate altitude (in hypobaric hypoxia) exhibit increased depression-like behavior, altered brain serotonin and a lack of antidepressant response to most selective serotonin reuptake inhibitors (SSRIs). A forebrain deficit in the bioenergetic marker creatine is noted in people living at altitude or with MDD. Methods: Rats housed at 4500 ft were given dietary creatine monohydrate (CRMH, 4% w/w, 5 weeks) vs. un-supplemented diet, and impact on depression-like behavior, brain bioenergetics, serotonin and SSRI efficacy assessed. Results: CRMH significantly improved brain creatine in a sex-based manner. At altitude, CRMH increased serotonin levels in the female prefrontal cortex and striatum but reduced male striatal and hippocampal serotonin. Dietary CRMH was antidepressant in the forced swim test and anti-anhedonic in the sucrose preference test in only females at altitude, with motor behavior unchanged. CRMH improved fluoxetine efficacy (20 mg/kg) in only males at altitude: CRMH + SSRI significantly improved male striatal creatine and serotonin vs. CRMH alone. Conclusions: Dietary CRMH exhibits sex-based efficacy in resolving altitude-related deficits in brain biomarkers, depression-like behavior and SSRI efficacy, and may be effective clinically for SSRI-resistant depression at altitude. This is the first study to link CRMH treatment to improving brain serotonin.

scholarly journals The Antidepressant-Like Effects of Shen Yuan in a Chronic Unpredictable Mild Stress Rat Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Ning Jiang ◽  
Haixia Wang ◽  
Hong Huang ◽  
Jingwei Lv ◽  
Guirong Zeng ◽  
...  
Keyword(s):  
Panax Ginseng ◽  
Forced Swim Test ◽  
Preference Test ◽  
Underlying Mechanism ◽  
Mild Stress ◽  
Chronic Unpredictable Mild Stress ◽  
Oxidative Markers ◽  
Immobility Time ◽  
Polygala Tenuifolia ◽  
Sucrose Preference Test

Depression is a common yet severe neuropsychiatric condition that causes imposes considerable personal, economic, and social burdens worldwide. Medicinal plant species (e.g., Panax ginseng and Polygala tenuifolia) demonstrate potent antidepressant-like effects with less toxicity and other side effects. Shen yuan prescription (SY), composed of Panax ginseng (GT) and Polygala tenuifolia (YT). The present study aimed to elucidate the effects of SY treatment on chronic unpredictable mild stress (CUMS) rats and study the underlying mechanism. Our results indicated that SY (67.5, 135, or 270 mg/kg) significantly reverses the depressive-like behaviors in rats with a 5-week CUMS exposure, as demonstrated by increased sucrose consumption in the sucrose preference test, and decreased immobility time in the tail suspension and forced swim test. Moreover, SY altered serum corticosterone levels, pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), and oxidative markers (SOD, CAT, and MDA), and increased the levels of hippocampal neurotransmitters (5-HT, DA, and NE) in rats exposed to CUMS. Furthermore, rats treated with SY showed a reduction in the protein expression of BDNF, p-TrkB, p-Akt, and p-mTOR proteins induced by CUMS exposure in the hippocampus. In conclusion, SY prevented depressive-like behaviors in CUMS-exposed rats by preventing hypothalamus-pituitary-adrenal axis dysfunction, decreasing the levels of the neurotransmitters, minimizing oxidative stress, suppressing neuroinflammation, and activating the PI3K/Akt/mTOR-mediated BDNF/TrkB pathway, all of which are the key players in the pathological basis of depression.

scholarly journals Additive Antidepressant Effects of Combined Administration of Ecitalopram and Caloric Restriction in LPS-Induced Neonatal Model of Depression in Rats

2020 ◽  
Vol 47 (4) ◽  
pp. 31-37
Author(s):  
E. Haritov ◽  
J. Tivcheva
Keyword(s):  
Caloric Restriction ◽  
Wistar Rats ◽  
Forced Swim Test ◽  
Behavioral Assessment ◽  
Preference Test ◽  
Elisa Method ◽  
Antidepressant Effects ◽  
New Strategy ◽  
Sucrose Preference Test ◽  
The Brain

AbstractBackground and aims: Increasing evidence indicates that inflammation in the periphery and neuroinflammation in the brain might be involved in the pathophysiology of depressive symptoms in humans. Relatively little is known about the effects of selective serotonin re-uptake inhibitors (SSRI) on individuals exposed to differential dietary regimens, like caloric restriction (CR).The aim of the current study is to assess the antidepressant and antineuroinflammatory effects of CR in single administration and combined with SSRIsantidepressant escitalopram in LPS-induced model of depression in Wistar rats.Materials and methods: For this purpose, we used 36 Wistar rats and applied 3 behavioral tests for depression (FST, SPT and NSFT) in animals and an ELISA-method for measurement of brain IL-1beta levels.Results: Behavioral assessment and results from ELISA-method have shown that CR not only augments the effect of the antidepressant escitalopram on forced swim test (FST) and sucrose preference test (SPT), but also reduces the brain levels of proinflammatory cytokine IL-1beta. Combined with escitalopram, CR enhances antidepressant and antinflamatory properties of this SSRI.Discussion and conclusion: These results show that the response to antidepressive treatment depends on the diverse dietary regimens, especially low-caloric diet. We suggest that the background of this is augmentation of anidepressant and antineuronflammatory properties of some antidepressants by CR. Manipulation of dietary regimens is attractive and new strategy for the management of pharmacoresistant depression.

scholarly journals Sex-Specific Social Effects on Depression-Related Behavioral Phenotypes in Mice

Life ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1327
Author(s):  
Seona Patel ◽  
Lindsay Cameron ◽  
David Olson
Keyword(s):  
Opposite Effect ◽  
Forced Swim Test ◽  
Preference Test ◽  
Well Being ◽  
Depression And Anxiety ◽  
Behavioral Deficits ◽  
Behavioral Phenotypes ◽  
Treatment Groups ◽  
Males And Females ◽  
Sucrose Preference Test

Social interaction and empathy play critical roles in determining the emotional well-being of humans. Stress-related depression and anxiety can be exacerbated or mitigated depending on specific social conditions. Although rodents are well known to exhibit emotional contagion and consolation behavior, the effects of group housing on stress-induced phenotypes in both males and females are not well established. Here, we investigated how the presence of stressed or unstressed conspecifics within a cage impact depression-related phenotypes. We housed male and female C57BL/6J mice in same-sex groups and subjected them to either gentle handling (GH) or the daily administration of corticosterone (CORT) for 10 days. The GH and CORT treatment groups were divided into cages of unmixed (GH or CORT) and mixed (GH and CORT) treatments. Depression-related phenotypes were measured using the forced swim test (FST) and sucrose preference test (SPT). We found that mixed housing alters FST behavior in a sex-specific manner. Male mice given chronic corticosterone (CORT) that were housed in the same cage as gently handled animals (GH) exhibited increased immobility, whereas GH females housed with CORT females demonstrated the opposite effect. This study underscores the importance of social housing conditions when evaluating stress-induced behavioral phenotypes and suggests that mixed cages of GH and CORT animals yield the greatest difference between treatment groups. The latter finding has important implications for identifying therapeutics capable of rescuing stress-induced behavioral deficits in the FST.

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