Hirami lemon (<i>Citrus reticulata</i> var. <i>depressa</i>) modulates the gut–brain axis in a chronic mild stress-induced depression mouse model

Tsai, Pi-Fang; Wu, Edmond H. C.; Li, Huiru; Senthilkumar, KL; Wang, S.-Y.

doi:10.1039/d3fo01301d

Cited by 7 publications

(4 citation statements)

References 63 publications

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“…The duration of immobility markedly decreased in animals administered a single dose of CBEO (25 mg/kg), indicating a rapid antidepressant effect. These results align with those of previous studies ( Tang et al, 2022 ; Tsai et al, 2023 ), although those studies required a longer treatment duration (one to six weeks) and higher doses (100–500 mg/kg for oral administration), suggesting an outstanding advantage of intranasal administration. Compared with other routes, intranasal delivery has been prominent in drug development in recent years owing to its rapid effects and high bioavailability by crossing the blood–brain barrier directly and avoiding the first-pass effect ( Shringarpure et al, 2021 ).…”

Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

“…According to a previous study, CBEO improves reserpine-induced depressive behavior, possibly by regulating the expression of brain-derived neurotrophic factors, glucocorticoid receptors, and 5-hydroxytryptamine-1A receptors ( Tang et al, 2022 ). Another study revealed that CBEO possessed antidepressant activity by modulating the gut microbiota ( Tsai et al, 2023 ). CBEO contains multiple components that exert its effects through various pathways.…”

Section: Introductionmentioning

confidence: 99%

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Antidepressant and anxiolytic potential of Citrus reticulata Blanco essential oil: a network pharmacology and animal model study

Khanh Nguyen,

Kwon,

Kim

et al. 2024

Front. Pharmacol.

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Background:Citrus reticulata Blanco essential oil (CBEO) has attracted increasing attention as a potential treatment for depression and anxiety in recent years. However, there is limited evidence regarding the active compounds responsible for its therapeutic effects. In addition, substantial amounts of CBEO and prolonged therapy are often required. This study aims to investigate the rapid acting antidepressant and anxiolytic effects of CBEO, identify the underlying composition as well as optimize its dosage and duration.Methods:CBEO composition was determined using gas chromatography–mass spectrometry (GC–MS), and the corresponding targets were obtained from the SwissTargetPrediction database. Depression-related targets were collected from DisGeNET, GeneCards, Therapeutic Target Database, and Online Mendelian Inheritance in Man. Subsequently, the overlap between CBEO and depression targets was utilized to build a network diagram depicting the relationship between the active ingredients and targets using Cytoscape software. The STRING database facilitated the construction of a protein–protein interaction network, and the Ma’ayan Laboratory Enrichment tool was employed for Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Wiki pathway analyses. Molecular docking was conducted using AutoDock Vina and Discovery Studio Visualizer. Topological analysis predicted the main antidepressant active ingredients in CBEO. A mixture of these compounds was prepared based on their relative GC–MS ratios. Tail suspension test, elevated plus maze, corticosterone-induced PC12 cells, and lipopolysaccharide (LPS)-induced BV2 cells were used to validate the antidepressant and anxiolytic potential of CBEO and CBEO’s main bioactive constituents.Results:CBEO contains 18 components that target 121 proteins. We identified 595 targets associated with depression; among them, 29 targets were located between essential oils and depression. Topological results revealed that linalool, p-cymene, α-terpinene, terpinen-4-ol, and α-terpineol were the major active compounds of CBEO in the management of depression. GO analysis identified G protein-coupled opioid receptor activity, phospholipase C-activating G protein-coupled receptor, and neuron projections that were mostly related to molecular functions, cellular components, and biological processes. Neuroactive ligand-receptor interactions, chemical carcinogenesis, and calcium signaling pathways were the major pathways identified in KEGG analysis. Molecular docking showed that the main bioactive ingredients of CBEO had favorable binding affinities for Protein-Protein Interaction’s hub proteins, including OPRM1, PTGS2, ESR1, SLC6A4, DRD2, and NR3C1. These five compounds were then mixed at 0.8:5:0.6:2:1 (w/w) ratio to form a CBEO antidepressant active compound mixture. An acute intranasal treatment of CBEO (25 mg/kg) only demonstrated an antidepressant effect, whereas the main bioactive compounds combination (12.5 mg/kg) illustrated both antidepressant and anxiolytic effects in mice. Linalool, p-cymene, and terpinene-4-ol exhibited neuroprotective and anti-neuroinflammation in the in vitro study, while these effects were not observed for α-terpinene and α-terpineol.Conclusion:Linalool, p-cymene, α-terpinene, terpinen-4-ol, and α-terpineol cymene might be mainly contributing to CBEO’s antidepressant effect by regulating neuroactive ligand-receptor interaction, neuron projection, and receptor signaling pathway. A mixture of these compounds showed rapid antidepressant potential via intranasal administration, which was comparable to that of CBEO. The mixture also exhibited an anxiolytic effect while not seen in CBEO.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

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Antidepressant and anxiolytic potential of Citrus reticulata Blanco essential oil: a network pharmacology and animal model study

Khanh Nguyen,

Kwon,

Kim

et al. 2024

Front. Pharmacol.

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“…The mice were gently placed in the water and allowed to swim freely for 6 min. 27 Mice that did not move at all or had only one paw to maintain balance and gently moved were considered motionless. The immobile time of the mice was recorded.…”

Section: Methodsmentioning

confidence: 99%

Long-term intake of thermo-induced oxidized oil results in anxiety-like and depression-like behaviors: involvement of microglia and astrocytes

Lu,

Shi,

et al. 2024

Food Funct.

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Reviews on Asian citrus species: Exploring traditional uses, biochemistry, conservation, and disease resistance

Palangasinghe,

Liyanage,

Wickramasinghe

et al. 2024

Ecological Genetics and Genomics

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Hirami lemon (Citrus reticulata var. depressa) modulates the gut–brain axis in a chronic mild stress-induced depression mouse model

Abstract: Citrus reticulata var. depressa, commonly known as Hirami lemon, is a native citrus species found in the Taiwan and Okinawa islands of Japan. While several Citrus species are known to...

Cited by 7 publications

References 63 publications

Antidepressant and anxiolytic potential of Citrus reticulata Blanco essential oil: a network pharmacology and animal model study

Antidepressant and anxiolytic potential of Citrus reticulata Blanco essential oil: a network pharmacology and animal model study

Long-term intake of thermo-induced oxidized oil results in anxiety-like and depression-like behaviors: involvement of microglia and astrocytes

Reviews on Asian citrus species: Exploring traditional uses, biochemistry, conservation, and disease resistance

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