The antidepressant effects of hesperidin on chronic unpredictable mild stress‐induced mice

ABSTRACT Hesperidin, a kind of citrus bioflavonoid distributed in foods including grapefruits, oranges and lemons, has many pharmacological activities. This study was aimed to evaluate the anti‐depressant‐like effect of hesperidin on chronic unpredictable mild stress (CUMS)‐induced mice. Depressive‐like behavior was detected by the sucrose preference test (SPT), tail suspension test (TST) and forced swimming test (FST). A 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2‐H‐tetrazolium bromide (MTT) assay was performed to assess the cell viability of corticosterone‐induced PC12 cells. The serum, hippocampal and cell supernatant concentrations of interleukin (IL)‐1&bgr;, IL‐6 and tumor necrosis factor (TNF)‐&agr; were determined using enzyme‐linked immunosorbent assay (ELISA) commercial kits. Furthermore, the protein expression levels of high‐mobility group box 1 protein (HMGB1), receptor for advanced glycation end‐products (RAGE)/NF‐&kgr;B and brain‐derived neurotrophic factor (BDNF)/tropomyosin‐related kinase B (TrkB) pathway in the hippocampus and corticosterone‐induced PC12 cells were detected by Western blot. Our results showed that hesperidin (100, 200 mg/kg) significantly relieved depressive‐like behaviors, including decreased sucrose consumption in sucrose preference test (SPT), immobility in the forced swimming test (FST), tail suspension test, and locomotor activity in the open field test (OFT). Hesperidin reduced inflammatory cytokine levels by attenuating the HMGB1/RAGE/NF‐&kgr;B signaling pathway and BDNF/TrkB pathway both in vivo and in vitro. In conclusion, hesperidin possessed efficient neuroprotective effects on depression, which was associated with neuroinflammation mediated by the HMGB1/RAGE/NF‐&kgr;B and BDNF/TrkB pathways.

• Publication year

  2019

• Venue

  European Journal of Pharmacology

• Publication date

  2019-06-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.ejphar.2019.03.035PMID 30928632
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Minocycline ameliorates depressive behaviors and neuro‐immune dysfunction induced by chronic unpredictable mild stress in the rat

  2019cited by this paper
• Persistent Increase in Microglial RAGE Contributes to Chronic Stress-Induced Priming of Depressive-like Behavior.

  2018cited by this paper
• Perilla aldehyde attenuates CUMS‐induced depressive‐like behaviors via regulating TXNIP/TRX/NLRP3 pathway in rats

  2018cited by this paper
• Interactions between pro-inflammatory cytokines and statins on depression in patients with acute coronary syndrome.

  2018cited by this paper
• The antidepressant effects of &agr;‐tocopherol are related to activation of autophagy via the AMPK/mTOR pathway

  2018cited by this paper
• Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice

  2018cited by this paper
• Glycyrrhizic acid ameliorates the kynurenine pathway in association with its antidepressant effect

  2018cited by this paper
• Can Ocimum basilicum relieve chronic unpredictable mild stress-induced depression in mice?

  2017cited by this paper
• The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman's disease.

  2017cited by this paper
• Antidepressants induce autophagy dependent‐NLRP3‐inflammasome inhibition in Major depressive disorder

  2017cited by this paper
• Rosiglitazone Exerts an Anti-depressive Effect in Unpredictable Chronic Mild-Stress-Induced Depressive Mice by Maintaining Essential Neuron Autophagy and Inhibiting Excessive Astrocytic Apoptosis

  2017cited by this paper
• Antidepressant-like Effect of Bacopaside I in Mice Exposed to Chronic Unpredictable Mild Stress by Modulating the Hypothalamic–Pituitary–Adrenal Axis Function and Activating BDNF Signaling Pathway

  2017cited by this paper
• HMGB1 mediates depressive behavior induced by chronic stress through activating the kynurenine pathway.

  2017cited by this paper
• Exercise increases serum brain-derived neurotrophic factor in patients with major depressive disorder.

  2017cited by this paper
• Anti‐atherosclerotic effect of hesperidin in LDLr−/− mice and its possible mechanism

  2017cited by this paper
• Cortical Plasticity in Depression

  2017cited by this paper
• HMGB1 regulates P-glycoprotein expression in status epilepticus rat brains via the RAGE/NF-κB signaling pathway

  2017cited by this paper
• Methyl Jasmonate Ameliorates Unpredictable Chronic Mild Stress‐Induced Behavioral and Biochemical Alterations in Mouse Brain

  2017cited by this paper
• Hesperidin derivative‐11 inhibits fibroblast‐like synoviocytes proliferation by activating Secreted frizzled‐related protein 2 in adjuvant arthritis rats

  2017cited by this paper
• Hesperidin reverses cognitive and depressive disturbances induced by olfactory bulbectomy in mice by modulating hippocampal neurotrophins and cytokine levels and acetylcholinesterase activity.

  2016cited by this paper
• Nine traditional Chinese herbal formulas for the treatment of depression: an ethnopharmacology, phytochemistry, and pharmacology review

  2016cited by this paper
• Dendritic Spines in Depression: What We Learned from Animal Models

  2016cited by this paper
• Hesperidin Alleviates Lipopolysaccharide-Induced Neuroinflammation in Mice by Promoting the miRNA-132 Pathway

  2016cited by this paper
• HMGB1 Induces an Inflammatory Response in the Chorioamniotic Membranes That Is Partially Mediated by the Inflammasome1

  2016cited by this paper
• Hesperidin alleviates cisplatin-induced hepatotoxicity in rats without inhibiting its antitumor activity

  2016cited by this paper
• Liquiritigenin reverses depression-like behavior in unpredictable chronic mild stress-induced mice by regulating PI3K/Akt/mTOR mediated BDNF/TrkB pathway.

  2016cited by this paper
• High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior.

  2015cited by this paper
• Geraniol produces antidepressant-like effects in a chronic unpredictable mild stress mice model.

  2015cited by this paper
• Involvement of normalized NMDA receptor and mTOR-related signaling in rapid antidepressant effects of Yueju and ketamine on chronically stressed mice

  2015cited by this paper
• Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial.

  2015cited by this paper
• Antidepressant-like effects of salidroside on olfactory bulbectomy-induced pro-inflammatory cytokine production and hyperactivity of HPA axis in rats.

  2014cited by this paper
• An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies.

  2014cited by this paper
• Anti-depressant effect of hesperidin in diabetic rats.

  2014cited by this paper
• Named Series : Diet , Inflammation and the Brain Diet-induced obesity progressively alters cognition , anxiety-like behavior and lipopolysaccharide-induced depressive-like behavior : Focus on brain indoleamine 2 , 3-dioxygenase activation

  2014cited by this paper
• Metabonomic Study on the Antidepressant-Like Effects of Banxia Houpu Decoction and Its Action Mechanism

  2013cited by this paper
• Management of Chronic Depressive Patients with Residual Symptoms

  2013cited by this paper
• Fluoxetine versus other types of pharmacotherapy for depression.

  2013cited by this paper
• Depression and inflammation: an intricate relationship.

  2012cited by this paper
• Hesperetin-7,3'-O-dimethylether selectively inhibits phosphodiesterase 4 and effectively suppresses ovalbumin-induced airway hyperresponsiveness with a high therapeutic ratio

  2011cited by this paper
• The Hippocampus, Neurotrophic Factors and Depression

  2011cited by this paper
• Reduced neurogenesis and pre-synaptic dysfunction in the olfactory bulb of a rat model of depression.

  2011cited by this paper
• Atorvastatin protects rat brains against permanent focal ischemia and downregulates HMGB1, HMGB1 receptors (RAGE and TLR4), NF-kappaB expression.

  2010cited by this paper
• Tanshinone II A down-regulates HMGB1, RAGE, TLR4, NF-kappaB expression, ameliorates BBB permeability and endothelial cell function, and protects rat brains against focal ischemia.

  2010cited by this paper
• Evidence for a cytokine model of cognitive function.

  2009cited by this paper
• Brain-derived neurotrophic factor, stress and depression: a minireview.

  2009cited by this paper
• Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress.

  2008cited by this paper

• Standardized Hericium erinaceus Extract Powder Improves Scopolamine-Induced Cognitive Deficits via BDNF-Mediated Neuroplasticity

  2026cites this paper
• Elucidating the Mechanism of the Liqi Yangyin Formula in Treating Depression–Constipation Comorbidity: An Integrative Approach Using Network Pharmacology and Experimental Validation

  2026cites this paper
• HESPERIDIN INHIBITS THE ACQUISITION AND EXPRESSION OF SENSITIZATION TO THE LOCOMOTOR STIMULANT EFFECT OF ETHANOL IN SWISS ALBINO MICE

  2026cites this paper
• Hesperidin reverses behavioral deficits and neurochemical disruptions in a single prolonged stress-induced PTSD rat model: targeting monoaminergic and GABAergic systems

  2025cites this paper
• Hesperidin Attenuates Chronic Stress-Induced Depression via 5-HT2A-Linked Modulation of Neurochemical, Oxidative, and Inflammatory Pathways: Experimental and In Silico Evidence

  2025cites this paper
• Decoding the neuroprotective potential of hesperidin: Insights into Alzheimer's disease.

  2025cites this paper
• trans-Resveratrol and Hesperidin Supplementation with Treadmill Exercise Alleviates Methylglyoxal-Induced Skeletal Muscle Dysfunction

  2025cites this paper
• The neuroprotective effects of hesperidin and diosmin in neurological disorders via targeting various signaling pathways

  2025cites this paper
• Antidepressant effects and mechanisms of Wuhua herbal tea in a rat model of chronic unpredictable mild stress

  2025cites this paper
• An updated and comprehensive review of the health benefits and pharmacological activities of hesperidin.

  2025cites this paper
• Neuroprotective Effects of a Combination of Dietary Trans-Resveratrol and Hesperidin Against Methylglyoxal-Induced Neurotoxicity in a Depressive Amnesia Mouse Model

  2025cites this paper
• Hesperidin in Chronic Fatigue Syndrome: An Integrated Analysis of Traditional Pharmacology and Machine Learning–Based Therapeutic Predictions

  2025cites this paper
• Preventive Effects of Hochuekkito on Decline in Brain-Derived Neurotrophic Factor Serum Levels in Senescence-Accelerated Mouse Prone 10.

  2025cites this paper
• HMGB1: Different secretion pathways with pivotal role in epilepsy and major depressive disorder.

  2025cites this paper
• A comprehensive review on the impact of polyphenol supplementation and exercise on depression and brain function parameters

  2025cites this paper
• Adolescent adversity persistently induces proinflammatory HMGB1 signaling and disrupts the basal forebrain cholinergic system in female rats

  2025cites this paper
• Liqi Yangyin formula ameliorates CUMS-induced depression and comorbid constipation via ACE/FFAR2 modulation of the microbiota-gut-brain axis

  2025cites this paper
• Du-moxibustion ameliorates depression-like behavior and neuroinflammation in chronic unpredictable mild stress-induced mice.

  2024cites this paper
• The Impacts of Hesperidin on Motor-Cognitive Disorders, Oxidative Damage, and Cholinergic Function in the Hippocampus of a Parkinson's Disease Rat Model

  2024cites this paper
• Exploring the Association between BDNF related Signaling Pathways and Depression: A Literature Review.

  2024cites this paper
• Interaction between Gut Microbiota and Medicinal Food Homology in Depression

  2024cites this paper
• Hesperidin alleviated dendritic spines through inhibiting ferritinophagy via HERC2-NCOA4 ubiquitination in CUMS mice.

  2024cites this paper
• Flavonoids against depression: a comprehensive review of literature

  2024cites this paper
• Vanillic Acid Protects PC12 Cells from Corticosterone-Induced Neurotoxicity via Regulating Immune and Metabolic Dysregulation Based on Computational Metabolomics

  2024cites this paper
• The Impact of Hesperidin on Cognitive Deficit and Neurobehavioural Disorders: A Systematic Review and Meta-Analysis of Preclinical Individual Studies

  2024cites this paper
• Natural products: A potential immunomodulators against inflammatory-related diseases

  2024cites this paper
• Effect of Hesperidin on Chronic Unpredictable Mild Stress-Related Depression in Rats through Gut-Brain Axis Pathway

  2024cites this paper
• Phytochemistry, pharmacological properties and pharmacokinetics of Citri Reticulatae Pericarpium: A systematic review.

  2024cites this paper
• Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease

  2024cites this paper
• Jiawei Dachaihu decoction protects against mitochondrial dysfunction in atherosclerosis (AS) mice with chronic unpredictable mild stress (CUMS) via SIRT1/PGC-1α/TFAM/LON signaling pathway.

  2024cites this paper
• Immunoregulatory role of hesperidin against ovalbumin (OVA)-induced bronchial asthma and depression in rats

  2023cites this paper
• Hepatoprotective and cognitive-enhancing effects of hesperidin against thioacetamide-induced hepatic encephalopathy in rats.

  2023cites this paper
• The benefits of hesperidin in central nervous system disorders, based on the neuroprotective effect.

  2023cites this paper
• Phytochemicals That Act on Synaptic Plasticity as Potential Prophylaxis against Stress-Induced Depressive Disorder

  2023cites this paper
• Neuroprotective Potentials of Flavonoids: Experimental Studies and Mechanisms of Action

  2023cites this paper
• Mass transfer mechanism of the multivariate consecutive extraction process of pectin and hesperidin from Citrus aurantium L.:Kinetics, Thermodynamics, Diffusion and Mass transfer coefficients

  2023cites this paper
• Bullatine A Has an Antidepressant Effect in Chronic Social Defeat Stress Mice; Implication of Microglial Inflammasome.

  2023cites this paper
• Prophylactic effect of Tongxieyaofang polysaccharide on depressive behavior in adolescent male mice with chronic unpredictable stress through the microbiome-gut-brain axis.

  2023cites this paper
• Polyphenols as novel interventions for depression: exploring the efficacy, mechanisms of action, and implications for future research.

  2023cites this paper
• HMGB1 in depression: An overview of microglial HMBG1 in the pathogenesis of depression

  2023cites this paper
• Serum levels of high mobility group box‐1 protein (HMGB1) and soluble receptors of advanced glycation end‐products (RAGE) in depressed patients treated with electroconvulsive therapy

  2023cites this paper
• Role of BDNF–TrkB signaling in the antidepressant‐like actions of loganin, the main active compound of Corni Fructus

  2023cites this paper
• The Indian Delicacy Nimbu Achar: Your Lemony Pathway to Brain Health

  2023cites this paper
• Hesperidin plays beneficial roles in disorders associated with the central nervous system: a review

  2023cites this paper
• Novel bisdemethoxycurcumin@phytomicelle ophthalmic solution: In vitro formulation appraisal and in vivo prompting rapid corneal wound healing evaluations.

  2023cites this paper
• Glucosyl hesperidin exhibits more potent anxiolytic activity than hesperidin accompanied by the attenuation of noradrenaline induction in a zebrafish model

  2023cites this paper
• Hesperidin reduces depressive symptoms in post‐coronary artery bypass graft patients with mild depression

  2023cites this paper
• Elucidating the Effect of hesperidin on Behavioral and biochemical markers of liver and kidney function in Sprague Dawley Rats

  2023cites this paper
• Targeting neuroinflammation by polyphenols: A promising therapeutic approach against inflammation-associated depression.

  2022cites this paper
• Inhibition of Connexin 36 attenuates HMGB1‐mediated depressive‐like behaviors induced by chronic unpredictable mild stress

  2022cites this paper
• Mixture of Tomato and Lemon Extracts Synergistically Prevents PC12 Cell Death from Oxidative Stress and Improves Hippocampal Neurogenesis in Aged Mice

  2022cites this paper
• Antidepressive Effect of Natural Products and Their Derivatives Targeting BDNF-TrkB in Gut–Brain Axis

  2022cites this paper
• Exploring the multifocal role of phytoconstituents as antidepressants.

  2022cites this paper
• Beneficial effects of natural flavonoids on neuroinflammation

  2022cites this paper
• Effect of Sopoongsan on Skin Inflammation and Hyperlocomotion in Socially Isolated Mice with Atopic Dermatitis

  2022cites this paper
• Neurological disorders of COVID-19: insights to applications of natural products from plants and microorganisms

  2022cites this paper
• Potential Psychoactive Effects of Microalgal Bioactive Compounds for the Case of Sleep and Mood Regulation: Opportunities and Challenges

  2022cites this paper
• Polyphenols in edible herbal medicine: targeting gut-brain interactions in depression-associated neuroinflammation

  2022cites this paper
• Multi-strain Probiotic Formulation Reverses Maternal Separation and Chronic Unpredictable Mild Stress-Generated Anxiety- and Depression-like Phenotypes by Modulating Gut Microbiome-Brain Activity in Rats.

  2022cites this paper
• Role of high mobility group box protein 1 in depression: A mechanistic and therapeutic perspective

  2022cites this paper
• Neuroinflammation and Mitochondrial Dysfunction Link Social Stress to Depression.

  2022cites this paper
• Expression of ghrelin or growth hormone secretagogue receptor in the brain of postpartum stress mice

  2021cites this paper
• Global survey of medicinal plants during lactation and postpartum recovery: evolutionary perspectives and contemporary health implications.

  2021cites this paper
• Citrus Polyphenols in Brain Health and Disease: Current Perspectives

  2021cites this paper
• Oridonin ameliorates depressive-like behaviors induced by chronic unpredictable mild stress in mice via TXNIP/NLRP3 signaling pathway

  2021cites this paper
• Saxagliptin ameliorated the depressive-like behavior induced by chronic unpredictable mild stress in rats: Impact on incretins and AKT/PI3K pathway.

  2021cites this paper
• Cerebrospinal fluid proteomics reveal potential protein targets of JiaWeiSiNiSan in preventing chronic psychological stress damage

  2021cites this paper
• Theacrine, a Potent Antidepressant Purine Alkaloid from a Special Chinese Tea, Promotes Adult Hippocampal Neurogenesis in Stressed Mice.

  2021cites this paper
• Fecal microbiota transplantation ameliorates stress-induced depression-like behaviors associated with the inhibition of glial and NLRP3 inflammasome in rat brain.

  2021cites this paper
• Stress-induced blood brain barrier disruption: molecular mechanisms and signaling pathways.

  2020cites this paper
• The Anti-Depressive Effects of Hesperidin and the Relative Mechanisms Based on the NLRP3 Inflammatory Signaling Pathway

  2020cites this paper
• Protective effects of maternal administration of curcumin and hesperidin in the rat offspring following repeated febrile seizure: Role of inflammation and TLR4.

  2020cites this paper
• Molecular and cellular basis of the anticancer activity of the prenylated flavonoid icaritin in hepatocellular carcinoma.

  2020cites this paper
• Flavonoids as therapeutic candidates for emotional disorders such as anxiety and depression

  2020cites this paper
• Molecular insights into the therapeutic promise of targeting HMGB1 in depression

  2020cites this paper
• Modulatory action of environmental enrichment on hormonal and behavioral responses induced by chronic stress in rats: hypothalamic renin-angiotensin system components.

  2020cites this paper
• The Antidepressant-Like Effects of Hesperidin in Streptozotocin‐Induced Diabetic Rats by Activating Nrf2/ARE/Glyoxalase 1 Pathway

  2020cites this paper
• Metabolic Impact of Flavonoids Consumption in Obesity: From Central to Peripheral

  2020cites this paper
• Antidepressant-Like Activity of Myelophil via Attenuation of Microglial-Mediated Neuroinflammation in Mice Undergoing Unpredictable Chronic Mild Stress

  2019cites this paper
• A comprehensive study of eriocitrin metabolism in vivo and in vitro based on an efficient UHPLC-Q-TOF-MS/MS strategy

  2019cites this paper
• HMGB1 involved in stress-induced depression and its neuroinflammatory priming role: a systematic review

  2019cites this paper