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

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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Effect of (4a) a novel 5-HT3 receptor antagonist on chronic unpredictable mild stress induced depressive-like behavior in mice: an approach using behavioral tests battery

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2013-0160 ◽

2015 ◽

Vol 26 (1) ◽

Cited By ~ 3

Author(s):

Yeshwant Kurhe ◽

Radhakrishnan Mahesh ◽

Deepali Gupta ◽

Devadoss Thangaraj

Keyword(s):

Lipid Peroxidation ◽

Forced Swim Test ◽

Preference Test ◽

Tail Suspension Test ◽

Brain Homogenate ◽

Therapeutic Interventions ◽

Mild Stress ◽

Behavioral Alterations ◽

Biochemical Alterations ◽

Immobility Time

AbstractThe inconsistent therapeutic outcome necessitates designing and identifying novel therapeutic interventions for depression. Hence, the present study deals with the investigation of antidepressant-like effects of a novel 5-HTAnimals were subjected to different stressors for a period of 28 days. On day 15 after the subsequent stress procedure, mice were administered with (4a) (2 and 4 mg/kg p.o.), escitalopram (10 mg/kg p.o.), or vehicle (10 mL/kg p.o.) until day 28 along with the CUMS. Thereafter, behavioral battery tests like locomotor score, sucrose preference test, forced swim test (FST), tail suspension test (TST), and elevated plus maze (EPM) were performed. Biochemical assays like lipid peroxidation, nitrite levels, reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) were estimated in the mice brain homogenate.(4a) Dose dependently attenuated the behavioral alterations by increasing the sucrose consumption, reducing the immobility time in FST and TST, increasing the open arm number of entries and time in EPM. Furthermore, biochemical alterations were reversed by (4a) as examined by reduced lipid peroxidation and nitrite levels and elevated antioxidant enzyme levels like GSH, catalase and SOD.(4a) exhibits antidepressant potential by reversing the CUMS induced behavioral and biochemical changes in mice.

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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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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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PERUBAHAN PERILAKU GROOMING DAN IMOBILITAS MENCIT BALB/C TERINDUKSI DEPRESI YANG DISUPLEMENTASI TEMPE SEBAGAI SUMBER PARAPROBIOTIK

JURNAL AGROTEKNOLOGI ◽

10.19184/j-agt.v14i01.14030 ◽

2020 ◽

Vol 14 (01) ◽

pp. 1

Author(s):

Vanessa Ardianty ◽

Brian Saputra Manurung

Keyword(s):

Forced Swim Test ◽

Chronic Mild Stress ◽

Tail Suspension Test ◽

Depression Symptoms ◽

Depression Symptom ◽

Mild Stress ◽

Immobility Time ◽

Depression Level ◽

The Common ◽

Probiotic Food

Depression, a mental disorder marked by sadness, anhedonia and increased fatigability, is becoming more common in this industry 4.0 era. Nowadays, depression affects approximately 322 million people around the world (more than 14 million in Indonesia) and gives major contribution to the rise of global burden of disease. Although antidepressant is considered the common treatment for depression, recent studies show a possibility to treat depression by altering gut microbiome of the patient, by giving them probiotic food. Tempeh is a globally well-known Indonesian paraprobiotic food which already proven to modulate gut microbiota. This research aimed to find out the effect of tempeh to depression symptom as expressed in Balb/c mice behaviors. The methods used was to feed tempeh or tempeh starter to mice which were depressed-induced by Unpredictable Chronic Mild Stress (UCMS) procedure. Parameter measured were depression level of the Balb/c mice based on immobility times and grooming durations acquired from tail suspension test, forced swim test, sucrose splash test and coat state score. The result showed that tempeh supplementation did not affect coat states and grooming durations but tend to improve immobility times of the Balb/c mice. Meanwhile, tempeh starter supplementation tends to improve the immobility time and kept coat state clean/tidy, but lowered grooming duration. In conclusion, supplementation of paraprobiotic tempeh, especially in starter form, tend to improve depression symptoms. Keywords: depression, mice, paraprobiotic, tempeh

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

Psychiatry Investigation ◽

10.30773/pi.2019.0189 ◽

2020 ◽

Vol 17 (4) ◽

pp. 283-291 ◽

Cited By ~ 2

Author(s):

Feyza Aricioğlu ◽

Canan Yalcinkaya ◽

Ceren Sahin Ozkartal ◽

Erdem Tuzun ◽

Serap Sirvanci ◽

...

Keyword(s):

Preference Test ◽

Receptor Protein ◽

Antidepressant Effect ◽

Albino Rats ◽

Depression Symptoms ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Nlrp1 Inflammasome ◽

Immobility Time ◽

Wistar Albino 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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Δ3,2-Hydroxybakuchiol Attenuates Depression in Multiple Rodent Models Possibly by Inhibition of Monoamine Transporters in Brain

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/1325141 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10

Author(s):

Gang Zhao ◽

Li-he Guo ◽

Wei Huang ◽

Jia-liang Hu

Keyword(s):

Forced Swim Test ◽

Tail Suspension Test ◽

Rat Striatum ◽

Mild Stress ◽

Monoamine Transporters ◽

Rodent Models ◽

Norepinephrine Concentration ◽

Antidepressant Effects ◽

Immobility Time ◽

Pheochromocytoma Pc12

Δ3,2-Hydroxybakuchiol is isolated fromPsoralea corylifolia (L.), which has therapeutic applications in traditional Chinese medicine. Our previous studies have showed that Δ3,2-hydroxybakuchiol inhibited the decreased activity of reserpinized mice, suggestive of its antidepressive potential. In this study, we explored the antidepressant profile of Δ3,2-hydroxybakuchiol in various rodent models and its possible monoamine-modulating mechanism. Δ3,2-Hydroxybakuchiol significantly reduced immobility time of mice in forced swim test and tail suspension test. Δ3,2-Hydroxybakuchiol also significantly increased sucrose consumption in chronic unpredictable mild stress (CUMS) rat model. Furthermore, isotope uptake study showed that Δ3,2-hydroxybakuchiol inhibited the activity of human dopamine transporter (DAT) and norepinephrine transporter (NET) in transporter-overexpressing pheochromocytoma (PC12) cells with IC50values similar to the potency of bupropion. Microdialysis showed that Δ3,2-hydroxybakuchiol increased dopamine and norepinephrine concentration in rat striatum. In summary, Δ3,2-hydroxybakuchiol exerts antidepressant effects on various types of depression models through a possible mechanism of monoamine transporter inhibition.

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ANTIDEPRESSANT-LIKE ACTIVITY OF FLOWERS OF TECOMELLA UNDULATA IN MICE SUBJECTED TO CHRONIC UNPREDICTABLE MILD STRESS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v12i1.28981 ◽

2019 ◽

Vol 12 (1) ◽

pp. 130

Author(s):

Dinesh Dhingra ◽

Deepak Deepak

Keyword(s):

Young Male ◽

Ethanol Extract ◽

Preference Test ◽

Tail Suspension Test ◽

Plasma Corticosterone ◽

Sucrose Preference ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Tecomella Undulata ◽

Plasma Nitrite

Objective: Flowers of Tecomella undulata have been reported to be a rich source of flavonoids such as rutin and quercetin. The present study was designed to evaluate the effect of ethanol extract of flowers of T. undulata on chronic unpredictable mild stress (CUMS)-induced depression in Swiss young male albino mice.Methods: The mice were subjected to CUMS for 21 successive days. Ethanol extract of the flowers (50, 100, and 200 mg/kg, p.o.) and fluoxetine (20 mg/kg, p.o.) per se was administered for 21 successive days to separate groups of unstressed and stressed mice. Tail suspension test (TST) and sucrose preference test were used to evaluate the effect of the extract on depression-like behavior in mice.Results: Extract of flowers of T. undulata (100 and 200 mg/kg) significantly decreased immobility period of stressed mice in TST, indicating significant antidepressant-like activity of the extract. Stress-induced reduced sucrose preference was significantly restored by the extract. There was no significant effect on locomotor activity of mice by the extract and fluoxetine. The extract significantly reversed stress-induced increase in brain malondialdehyde levels; plasma nitrite and corticosterone levels; and also significantly reversed the stress-induced decrease in reduced glutathione and catalase levels. There was no significant effect of the extract on brain MAO-A activity in both unstressed and stressed mice.Conclusion: These results indicated that ethanol extract of flowers of T. undulata showed significant antidepressant-like activity in mice subjected to CUMS, probably through alleviation of oxidative stress and decrease in plasma corticosterone levels.

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Putative Role of Monoaminergic Systems in Antidepressant and Anxiolytic Effects of Naringin in Mice: An Interaction Study with Receptor Antagonists

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i47b33168 ◽

2021 ◽

pp. 661-676

Author(s):

G. E. Anyanwu ◽

V. O. Atuadu ◽

B. Ben-Azu ◽

E. A. Esom ◽

J. N. Nto ◽

...

Keyword(s):

Anxiolytic Effect ◽

Preference Test ◽

Tail Suspension Test ◽

Receptor Interaction ◽

Control Group ◽

Mild Stress ◽

Receptor Antagonists ◽

Neurotransmitter Receptor ◽

Immobility Time

Aim: Stress-related disorders like depression and anxiety represent one of the greatest therapeutic challenges globally. Although previous studies have revealed the antidepressant-like potentials of naringin, the neurotransmitter receptor interaction mechanisms of action have not been studied, hence, this study was carried out to evaluate the role of neurotransmitter-receptor antagonists in the antidepressant-like effects of naringin in mice. Method: Male Swiss mice were subjected to chronic unpredictable mild stress (CUMS) apart from mice in the control group. The mice were then pretreated with different neurotransmitter antagonists; metergoline (4 mg /kg i.p.), a 5-HT1 - and 5-HT2 -receptor antagonist; propranolol; (0.2 mg/kg i.p.), β1,2-noradrenoceptor antagonist or haloperidol (0.2 mg/kg i.p.), D 2 -dopaminergic receptor antagonists prior to the administration of naringin or vehicle (10 mL/kg). The antidepressant-like and anxiolytic effects of naringin were evaluated 30 min later using the tail suspension test (TST), open-field test (OFT), sucrose preference test (SPT) and elevated plus maze (EPM) tests paradigms. Results: Administration of naringin following CUMS significantly decrease immobility time and locomotion activity in TST and OFT respectively, relative to control while increasing preference to sucrose in SPT, open arm entries as well as time spent in open arm in EPM, relative to control suggesting antidepressant-like property. Pretreatment with metergoline, propranolol, and haloperidol following CUMS increased immobility time in TST, locomotor activity in OFT and IOAA in the EPM. Reduced preference for sucrose in SPT, open arm entry and duration in EPM relative to control (p < 0.05), however, these effects were attenuated by naringin. Conclusion: These findings suggest that the antidepressant-like activity exhibited by naringin might be mediated via interactions with 5-HTergic, noradrenergic, and dopaminergic receptors, while the anxiolytic effect might involve interaction with both 5-HTergic and noradrenergic receptors.

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Jianpi Jieyu Decoction, An Empirical Herbal Formula, Exerts Psychotropic Effects in Association With Modulation of Gut Microbial Diversity and GABA Activity

Frontiers in Pharmacology ◽

10.3389/fphar.2021.645638 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lanying Liu ◽

Zhilu Zou ◽

Jiangwei Yang ◽

Xiaoqi Li ◽

Boran Zhu ◽

...

Keyword(s):

Serum Level ◽

Gut Microbiota ◽

Forced Swim Test ◽

Preference Test ◽

Tail Suspension Test ◽

Antidepressant Effect ◽

Mild Stress ◽

Gamma Aminobutyric Acid ◽

Object Recognition Test ◽

Microbial Distribution

Background: Recent studies suggest that gut microbiota was associated with the bidirectional gut-brain axis which could modulate neuropsychological functions of the central nervous system. Gut microbiota could produce gamma aminobutyric acid (GABA) that could modulate the gut–brain axis response. Jianpi Jieyu (JPJY) decoction, a traditional Chinese formula, is mainly composed of Astragalus membranaxeus and Radix Pseudostellariae. Although the JPJY decoction has been used to treat the depression in China, the potential action of its antidepressant has not been well understood. Thus this study was aim to investigate the role of JPJY improve gut microbiota homeostasis in the chronic stress induced depressive mice.Methods: The antidepressant effect of JPJY on chronic unpredictable mild stress (CUMS) mice was evaluated by using sucrose preference test, tail suspension test and forced swim test. Fatigue-like behaviors were evaluated using degree of redness, grip strength test, and exhaustive swimming test. The new object recognition test was used to evaluate cognition performance. Fecal samples were collected and taxonomical analysis of intestinal microbial distribution was conducted with 16S rDNA. Serum level of GABA was measured using high performance liquid chromatography (HPLC). The expression of GluR1 and p-Tau protein in the hippocampus was determined using Western blotting.Results: The dose of 9.2 g/kg JPJY produced antidepressant-like effects. JPJY and its major components also modulated gut microbiota diversity in the CUMS mice. Serum level of GABA and the expressions of hippocampal GluR1 and p-Tau were reversed after the administration of JPJY in CUMS mice.Conclusion: JPJY regulates gut microbiota to produce antidepressant-like effect and improve cognition deficit in depressive mice while its molecular mechanism possibly be enhanced NR1 and Tau expression in hippocampus and increased GABA in serum.

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Antidepressant Like Effect of Sodium Orthovanadate in A Mouse Model of Chronic Unpredictable Mild Stress.

10.21203/rs.3.rs-643262/v1 ◽

2021 ◽

Author(s):

Angel Joshi ◽

Ansab Akhtar ◽

Priyanka Saroj ◽

Anurag Kuhad ◽

Sangeeta Pilkhwal Sah

Keyword(s):

Molecular Mechanisms ◽

Nitrosative Stress ◽

Tyrosine Phosphatase ◽

Preference Test ◽

Tail Suspension Test ◽

Mild Stress ◽

Chronic Unpredictable Mild Stress ◽

Sodium Orthovanadate ◽

Behavioral Tests ◽

Oxidative And Nitrosative Stress

Abstract Depression is a psychiatric disorder characterized by low esteem, anhedonia, social deficit, and lack of interest. Decreased BDNF and impaired TrKB signaling be associated with depression. In our study, depressive-like behavior was induced in mice by chronic unpredictable mild stress (CUMS) model. Various behavioral tests like tail suspension test (TST), open field test (OFT), and sucrose preference test (SPT); biochemical analyses for corticosterone, reduced glutathione (GSH), lipid peroxidation (LPO), superoxide dismutase (SOD), nitric oxide (NO) and ELISA for BDNF were performed. Body weight was measured every week. Depressive-like behavior was associated with increased oxidative stress in the brain and subsequent reduction of BDNF. Further, sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor was used as a test drug as it is reported to stimulate BDNF levels. Sodium orthovanadate (SOV-5 mg/kg, 10 mg/kg) and fluoxetine (10 mg/kg) was given to mice orally for 21 days before 30 minutes of stress induction. The behavioral tests reflected depressive-like behavior in CUMS, which was attenuated by both SOV and fluoxetine. SOV at 10 mg/kg has demonstrated significant results in our study by decreasing malondialdehyde levels (MDA/LPO), NO levels, and increasing GSH and SOD in both the cortex and hippocampus. Besides, ELISA revealed the elevation of BDNF levels in the treatment groups (SOV-5 mg/kg, 10 mg/kg, and FLX-10 mg/kg) as compared with the disease group (CUMS). Therefore, the treatment with SOV appeared to reverse both oxidative and nitrosative stress. Decreased serum corticosterone levels (SOV-5 mg/kg, 10 mg/kg); FLX (10 mg/kg) + SOV (5 mg/kg); FLX-10 mg/kg and per-se) and elevated BDNF level (SOV-5 mg/kg, 10 mg/kg and FLX-10 mg/kg) were associated with attenuation of depressive-like behavior. The findings of this preliminary study indicate that SOV has the potential to restore antidepressant-like effect or prevention of stress-induced anhedonia and so further molecular mechanisms will be warranted for clinical translation.

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