NLRP1-Mediated Antidepressant Effect of Ketamine in Chronic Unpredictable Mild Stress Model in Rats

Objective NOD-like receptor protein 1 (NLRP1) inflammasome complex has been recently associated with chronic unpredictable mild stress (CUMS) model of depression. Our aim was to investigate whether ketamine-induced antidepressant effect is associated with suppression of NLRP1.Methods Wistar albino rats were divided into control, CUMS, CUMS+acute ketamine (a single 10 mg/kg dose) and CUMS+chronic ketamine (daily 10 mg/kg injections for 3 weeks) groups (n=10 for each group). Sucrose preference test and forced swimming test were performed to assess anhedonia and immobility time respectively for the severety of depression symptoms. Brain tissues were dissected and prefrontal cortex and hippocampus regions were used for real-time polymerase chain reaction (PCR) and immunohistochemical analysis.Results CUMS procedure significantly induced depressive-like symptoms whereas both acute and chronic ketamine treatment ameliorated them. mRNA expression levels of NLRP1, caspase 1, apoptosis-associated speck-like protein containing a CARD (ASC), NF-κB, endothelial nitric oxide synthase, IL-1β, IL-6, toll-like receptor 4 (TLR-4) and purinergic 2×7 receptor (P2X7R) and numbers of Iba- 1+and GFAP+glial cells were reduced by acute and/or chronic ketamine treatment.Conclusion In the present study for the first time upstream and downstream elements of the NLRP1 inflammasome complex are shown to be suppressed by ketamine thus reinforcing the involvement of NLRP1 in the physiopathology of depression.

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The Combination of Aquilaria sinensis (Lour.) Gilg and Aucklandia costus Falc. Volatile Oils Exerts Antidepressant Effects in a CUMS-Induced Rat Model by Regulating the HPA Axis and Levels of Neurotransmitters

Frontiers in Pharmacology ◽

10.3389/fphar.2020.614413 ◽

2021 ◽

Vol 11 ◽

Author(s):

Huiting Li ◽

Yuanhui Li ◽

Xiaofei Zhang ◽

Guilin Ren ◽

Liangfeng Wang ◽

...

Keyword(s):

Hpa Axis ◽

Central Area ◽

Preference Test ◽

Volatile Oil ◽

Antidepressant Effect ◽

Mild Stress ◽

Aquilaria Sinensis ◽

Immobility Time ◽

The Central Nervous System ◽

Sucrose Preference Test

The Aquilaria sinensis (Lour.) Gilg (CX)–Aucklandia costus Falc. (MX) herbal pair is frequently used in traditional Chinese medicine prescriptions for treating depression. The volatile oil from CX and MX has been shown to have good pharmacological activities on the central nervous system, but its curative effect and mechanism in the treatment of depression are unclear. Therefore, the antidepressant effect of the volatile oil from CX–MX (CMVO) was studied in chronic unpredictable mild stress (CUMS) rats. The suppressive effects of CMVO (25, 50, 100 μL/kg) against CUMS-induced depression-like behavior were evaluated using the forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT). The results showed that CMVO exhibited an antidepressant effect, reversed the decreased sugar preference in the SPT and prolongation of immobility time in the FST induced by CUMS, increased the average speed, time to enter the central area, total moving distance, and enhanced the willingness of rats to explore the environment in the OFT. Inhalational administration of CMVO decreased levels of adrenocorticotropic hormone and corticosterone in serum and the expression of corticotropin-releasing hormone mRNA in the hypothalamus, which indicated regulation of over-activation of the hypothalamic–pituitary–adrenal (HPA) axis. In addition, CMVO restored levels of 5-hydroxytryptamine (5-HT), dopamine, norepinephrine and acetylcholine in the hippocampus. The RT-PCR and immunohistochemistry results showed that CMVO up-regulated the expression of 5-HT1A mRNA. This study demonstrated the antidepressant effect of CMVO in CUMS rats, which was possibly mediated via modulation of monoamine and cholinergic neurotransmitters and regulation of the HPA axis.

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Electroacupuncture Prevents the Depression-Like Behavior by Inhibiting the NF-κB/NLRP3 Inflammatory Pathway in Hippocampus of Mice Subjected to Chronic Mild Stress

Neuropsychobiology ◽

10.1159/000521185 ◽

2022 ◽

pp. 1-9

Author(s):

Qi Wang ◽

Hongsheng Bi ◽

Hongfei Huang ◽

Yitong Wang ◽

Lili Gong ◽

...

Keyword(s):

Chronic Mild Stress ◽

Preference Test ◽

Underlying Mechanism ◽

Sucrose Preference ◽

Receptor Protein ◽

Mild Stress ◽

Inflammatory Pathway ◽

Protein Levels ◽

Tnf Α ◽

Immobility Time

Background: The precise physiological mechanisms of acupuncture in the treatment of depression are still unknown. This study aimed to observe the effects of electroacupuncture (EA) on depression-like behavior of mouse in chronic mild stress (CMS) model and explore the underlying mechanism. Methods: The depression model was established by using CMS method for 6 weeks. After the third week of the CMS paradigm, EA treatment was performed daily for 15 min over a period of 3 weeks. The antidepressant-like effects of EA were evaluated using the sucrose preference test and the forced swimming test (FST). The protein levels of the nuclear factor-kappa B (NF-κB), p-NF-κB, inhibitor of NF-κB, p-IκBα, NOD-like receptor protein 3, interleukin (IL)-6, IL-1β, IL-18, and tumor necrosis factor-α (TNF-α) in hippocampus of mice were detected. Results: Sucrose preference was decreased after 6 weeks of CMS and the effects of CMS was reversed by EA. CMS increased immobility time and decreased latency to the first immobility in the FST test, but these effects were reversed by EA. CMS-induced nuclear entry of NF-κB (nuclear/cytoplasmic ratio of NF-κB) with an increase in protein levels of p-NF-κB and p-IκBα in the hippocampus. The CMS also increased NLRP3 levels in the hippocampus. However, these effects were reversed by EA. In addition, the levels of IL-6, IL-1β, IL-18, and TNF-α in the hippocampus were increased by CMS, and these effects of stress were reversed by EA. Conclusion: EA prevented CMS-induced depressive-like behaviors by inhibiting NF-κB/NLRP3 inflammatory pathway.

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Oral supplementation with geranium oil or anise oil ameliorates depressed rat-related symptoms through oils antioxidant effects

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2019-0028 ◽

2019 ◽

Vol 17 (2) ◽

Cited By ~ 1

Author(s):

Karima A. El-Shamy ◽

Khaled M. M. Koriem ◽

Nevein N. Fadl ◽

Marwa H. A. El-Azma ◽

Mahmoud S. S. Arbid ◽

...

Keyword(s):

Cerebral Cortex ◽

Oral Intake ◽

Chronic Mild Stress ◽

Preference Test ◽

Tail Suspension Test ◽

Psychiatric Disease ◽

Albino Rats ◽

Mild Stress ◽

Immobility Time ◽

Antioxidant Effects

AbstractBackgroundDepression is a psychiatric disease condition and the chronic mild stress (CMS) model is a well-known and valuable animal model of depression. Geranium oil and anise oil were chosen for such a study. The aim of this research was to establish the geranium oil and anise oil effect to ameliorate CMS-related symptoms.MethodsThis research included 80 male albino rats each group of 10 rats and the animals were divided into two major groups: normal and CMS. The normal group was subdivided into four (control, geranium oil, anise oil and venlafaxine drug) subgroups treated orally with saline, geranium oil, anise oil and venlafaxine drug, respectively, for 4 weeks. The CMS group was subdivided into four (CMS without any treatment, CMS + geranium oil, CMS + anise oil and CMS + venlafaxine drug) subgroups treated orally with geranium oil, anise oil and venlafaxine drug, respectively, for 4 weeks.ResultsThe sucrose consumption in sucrose preference test, the distance traveled test and center square entries test were decreased, while center square duration test, immobility time in tail suspension test and floating time in forced swimming test were increased in CMS. The superoxide dismutase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and catalase levels decreased but malondialdehyde and nitric oxide levels increased in brain cerebral cortex and hippocampus areas in CMS. The oral intake of geranium oil and anise oil pushes all these parameters to approach the control levels. These results were supported by histopathological investigations of both brain cerebral cortex and hippocampus tissues.ConclusionsGeranium oil and anise oil ameliorate CMS-related symptoms and this effect were related to the antioxidant effects of oils.

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The Antidepressant Effect ofAngelica sinensisExtracts on Chronic Unpredictable Mild Stress-Induced Depression Is Mediated via the Upregulation of the BDNF Signaling Pathway in Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/7434692 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Jun Shen ◽

Junjian Zhang ◽

Min Deng ◽

Yue Liu ◽

Yuan Hu ◽

...

Keyword(s):

Signaling Pathway ◽

Preference Test ◽

Camp Response Element Binding ◽

Sucrose Preference ◽

Antidepressant Effect ◽

Force Swim Test ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Traditional Chinese Herbal Medicine ◽

Bdnf Signaling

Angelica sinensis(AS), a traditional Chinese herbal medicine, has pharmaceutical effects on menstrual illness, cerebrovascular diseases, cardiovascular diseases, and cognitive impairments. However, until recently, few studies had explored its antidepressant effect. The current study attempts to investigate the effect of AS extracts on chronic unpredictable mild stress- (CUMS-) induced depression in rats. Male SD rats were exposed to a CUMS-inducing procedure for 5 weeks, resulting in rodent depressive behaviors that included reduced sucrose consumption and lessened sucrose preference ratios in sucrose preference test, prolonged immobility times and decreased struggling time in force swim test, and decreased locomotor activity in open field test. Moreover, the expression of brain derived neurotrophic factor (BDNF) and the phosphorylation of cAMP-response element binding protein (CREB) and extracellular signal-regulated protein kinase (ERK 1/2) were markedly decreased in the hippocampus in depressed rats. However, chronically treating the depressed rats with AS (1 g/kg) normalized their depression-related behaviors and molecular profiles. In conclusion, in the present study, we show that AS extracts exerted antidepressant effects that were mediated by the BDNF signaling pathway: in AS-treated depressed rats, the expression of the BDNF protein and the phosphorylation of its downstream targets (ERK 1/2, CREB) were upregulated in the hippocampus.

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Escitalopram Targets Oxidative Stress, Caspase-3, BDNF and MeCP2 in the Hippocampus and Frontal Cortex of a Rat Model of Depression Induced by Chronic Unpredictable Mild Stress

International Journal of Molecular Sciences ◽

10.3390/ijms22147483 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7483

Author(s):

Vlad Dionisie ◽

Adela Magdalena Ciobanu ◽

Vlad Alexandru Toma ◽

Mihnea Costin Manea ◽

Ioana Baldea ◽

...

Keyword(s):

Oxidative Stress ◽

Frontal Lobe ◽

Caspase 3 ◽

Preference Test ◽

Sucrose Preference ◽

Fixed Dose ◽

Antidepressant Effect ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Sucrose Preference Test

In recent years, escitalopram (ESC) has been suggested to have different mechanisms of action beyond its well known selective serotonin reuptake inhibition. The aim of this study is to investigate the effects of escitalopram on oxidative stress, apoptosis, brain-derived neurotrophic factor (BDNF), Methyl-CpG-binding protein 2 (MeCP2), and oligodendrocytes number in the brain of chronic unpredictable mild stress-induced depressed rats. The animals were randomised in four groups (8 in each group): control, stress, stress + ESC 5 and stress + ESC 5/10. ESC was administered for 42 days in a fixed dose (5 mg/kg b.w.) or in an up-titration regimen (21 days ESC 5 mg/kg b.w. then 21 days ESC 10 mg/kg b.w.). Sucrose preference test (SPT) and elevated plus maze (EPM) were also performed. ESC improved the percentage of sucrose preference, locomotion and anxiety. ESC5/10 reduced the oxidative damage in the hippocampus and improved the antioxidant defence in the hippocampus and frontal lobe. ESC5/10 lowered caspase 3 activity in the hippocampus. Escitalopram had a modulatory effect on BDNF and the number of oligodendrocytes in the hippocampus and frontal lobe and also improved the MeCP2 expressions. The results confirm the multiple pathways implicated in the pathogenesis of depression and suggest that escitalopram exerts an antidepressant effect via different intricate mechanisms.

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Crassifoside H ameliorates depressant behavior in chronic unpredictable mild stress rats by improving HPA axis dysfunction and inhibiting inflammation in hippocampus

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i8.18 ◽

2020 ◽

Vol 19 (8) ◽

pp. 1693-1699

Author(s):

Huina Li ◽

Kefan Wu ◽

Yue Zhang ◽

Ning Li ◽

Kaijin Wang

Keyword(s):

Hpa Axis ◽

Mechanism Of Action ◽

Therapeutic Potential ◽

Preference Test ◽

Antidepressant Effect ◽

Enzyme Linked Immunosorbent Assay ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Tnf Α ◽

Sucrose Preference Test

Purpose: To investigate the antidepressant mechanism of action of Crassifoside H (CH) from the rhizomes of Curculigo glabrescens (Hypoxidaceae) in chronic unpredictable mild stress (CUMS)-induced rats.Methods: CUMS-induced rat depressant model was established. Behavioral tests, viz, sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST) were applied to assess the antidepressant effect of CH. Enzyme linked immunosorbent assay (ELISA) was used to assess thelevels of corticosterone (CORT), TNF-α and IL-1β in serum. Protein expressions of TNF-α, IL-1β and NLRP3 in rat hippocampus were determined by Western blot.Results: Crassifoside H significantly ameliorated CUMS-induced depressant-like behavior as the serum CORT level of CUMS rats. CH remarkably decreased TNF-α and IL-1β levels in serum and hippocampus of CUMS rats. Moreover, Crassifoside H significantly inhibited NLRP3 activation inhippocampus.Conclusion: The findings demonstrate that Crassifoside H has antidepressant effect on CUMS rats. The mechanism of action of CH may be at least partly due to the improvement of hypothalamic-pituitaryadrenal (HPA) axis dysfunction by decreasing serum CORT. These findings suggest that Crassifoside H has a therapeutic potential for the management of depression. Keywords: Crassifoside H, Antidepression, Curculigo glabrescens, Hypoxidaceae, Hypothalamicpituitary- adrenal axis, Inflammation, Corticosterone

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

Frontiers in Psychiatry ◽

10.3389/fpsyt.2021.622204 ◽

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.

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FGF21 restores hippocampual mitochondrial dysfunction via enhancing Nrf2/HO-1 and AMPK/SirT1/PGC-1α signaling pathways to alleviate chronic unpredictable mild stress induced depressive like behaviors in mice

10.21203/rs.3.rs-1003374/v1 ◽

2021 ◽

Author(s):

Yun-Tao Zhao ◽

Ling Shen ◽

Yong-Ping Zhang ◽

Lulu Zhang ◽

Leigang Jin ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Signaling Pathways ◽

Forced Swim Test ◽

Preference Test ◽

Tail Suspension Test ◽

Expression Level ◽

Fibroblast Growth Factor 21 ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Immobility Time

Abstract Mitochondrial dysfunction plays a key role in the pathogenesis of depression. Ample research proves mitochondria are a promising target for depression. Fibroblast growth factor 21 (FGF21) exerts roles in neuroprotection and could enhance mitochondria function. Here, the anti-depressive effect of FGF21 was evaluated on a chronic unpredictable mild stress (CUMS)- induced model of depression. The depressive-like behaviors were assessed using sucrose preference test (SPT), forced swim test (FST) and tail suspension test (TST). The results showed that treatment of FGF21 significantly attenuated the decrease in SPT, and dramatically reduced the immobility time in the TST and FST. These effects were associated with enhanced hippocampal mitochondrial function, reflected by FGF21-induced increases in mitochondrial ATP concentration, mitochondrial membrane potential (MMP), and decrease of reactive oxygen species (ROS) levels. At the same time, FGF21 ameliorated oxidative stress in CUMS-exposed mice by enhancing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase activities, and reducing malondialdehyde (MDA) level in the hippocampus. Mechanistically, we found that CUMS treatment decreased expression level of mitochondrial fusion protein 1 (MFN1), and increased expression level of mitochondrial dynamin-related protein 1 (DRP1). FGF21 administration increased expression of MFN1, and reduced expression of DRP1. Meanwhile, FGF21 treatment promoted the expression levels of Nrf2, HO-1, phosphorylated AMPK, SirT1, PGC-1a in the hippocampus. This study revealed that FGF21 alleviates CUMS induced depressive like behaviors by restoring mitochondria function via enhancing Nrf2/HO-1 and AMPK/SirT1/PGC-1α signaling pathways. It suggested that FGF21 would be a potential therapeutic agent in the management of depression.

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L. Cucurbita pepo Alleviates Chronic Unpredictable Mild Stress via Modulation of Apoptosis, Neurogenesis, and Gliosis in Rat Hippocampus

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6662649 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Nasra Ayuob ◽

Soad Ali Shaker ◽

Etedal Hawuit ◽

Nouf saeed Al-Abbas ◽

Nehad A. Shaer ◽

...

Keyword(s):

Cucurbita Pepo ◽

Positive Control ◽

Negative Control ◽

Albino Rats ◽

Histological Structure ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Potential Efficacy ◽

Immobility Time ◽

Nutritional Compounds

Pumpkin has received significant attention due to its nutritional compounds that have antioxidant, antifatigue, and anti-inflammatory effects. This study is aimed at assessing the antidepressant-like effect of L. Cucurbita pepo, sweet pumpkin, in an animal model of chronic unpredictable mild stress (CUMS) and investigating its effect on the histological structure of hippocampus compared to fluoxetine. Forty male albino rats assigned into the negative control, positive control (CUMS), and Flu-treated and pumpkin-treated groups ( n = 10 ) were utilized in this study. Exposing rats to CUMS continued for 28 days, and treatments used were applied during the last 14 days of exposure. Behavioral, biochemical, and histopathological changes were assessed after 28 days. In this study, pumpkin significantly reduced the immobility time ( p = 0.02 ), corticosterone ( p < 0.001 ), TNF-α, IL-6 ( p < 0.001 ), and malondialdehyde ( p = 0.003 ), whereas it significantly increased the level of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) in the serum of rats exposed to CUMS. Pumpkin markedly relieved the degenerative and atrophic changes observed in the CA3 region and the dentate gyrus of the hippocampus. It significantly reduced caspase-3 and increased glial fibrillary acidic protein (GFAP) immunoexpression in the CA3 and DG. In conclusion, administration of pumpkin extract improved the behavioral, biochemical, and hippocampal pathological alternations induced in rats after exposure to CUMS in a comparable pattern to fluoxetine. This study highlighted the potential efficacy of pumpkin in alleviating depression disorder either alone or in conjugation with conventional antidepressant therapy.

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Harmane suppresses microglial neuroinflammatory response and induce antidepressant-like effect in rats

European Psychiatry ◽

10.1016/j.eurpsy.2017.02.368 ◽

2017 ◽

Vol 41 (S1) ◽

pp. S366-S366 ◽

Cited By ~ 1

Author(s):

F. Aricioglu ◽

G. Arkan ◽

C. Kandemir ◽

S. Sirvanci ◽

C. Ozkartal ◽

...

Keyword(s):

Forced Swim Test ◽

Chronic Administration ◽

Immunohistochemical Analysis ◽

Sucrose Preference ◽

Antidepressant Effect ◽

Albino Rats ◽

Mild Stress ◽

Imidazoline Receptors ◽

Competing Interest ◽

Wistar Albino Rats

ObjectiveHarmane is a beta-carboline, which binds to imidazoline receptors and it has been previously shown that it may have an antidepressant effect when administered acutely. This study is planned to investigate the effect of harmane on chronic unpredictable mild stress (CUMS) model and microglial (Iba-1) immunoreactivity in the same model as markers of neuroinflammation.MethodsMale Wistar Albino rats (290–360 g) were divided into groups such as control (saline), CUMS, CUMS + Imipramine (20 mg/kg; i.p.), CUMS + Harmane5 (5 mg/kg; i.p.), CUMS + Harmane10 (10 mg/kg; i.p.) groups (n = 10–12 in each). In CUMS model, various stressors were applied for 40 days. On day 20, harmane administration was started for 20 days. At the end, sucrose preference and forced swimming tests were performed. Then, brains were removed with paraformaldehyde perfusion for Iba-1 immunohistochemical analysis in hippocampus. One-way analysis of variance and Tukey's test were used for statistical analysis.ResultsThe time of immobility in forced swim test was significantly reduced while sucrose preference was increased in Imipramine and CUMS + harmane10 groups. In immunohistochemical experiments, Iba-1 were overexpressed in CUMS group and Harmane significantly reduced the overexpression of Iba-1.ConclusionOur results suggest that chronic administration of harmane has an antidepressant-like activity in chronic stress model of depression. These results support the notion of imidazoline receptors involvement in depression by modulating neuroinflammation and at least a part of its antidepressant effect might be through modulating microglial activation as a reflection of neuroinflammation.This research was supported by Marmara University, Scientific Research Projects – SAG-C-YLP-110915-0415 and SAG-E-120613-0233.Disclosure of interestThe authors have not supplied their declaration of competing interest.

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