Research Progress on the Basic Pharmacodynamic Substance and Mechanism of Citri Sarcodactylis Fructus in Relieving Anxiety

Ting Chen

doi:10.62767/jecacm501.1395

Authors

Ting Chen Zhejiang Chinese Medical University, 310053 Hangzhou, Zhejiang, China Author

DOI:

https://doi.org/10.62767/jecacm501.1395

Keywords:

Citri Sarcodactylis Fructus, bergamot essential oil, anti-anxiety, anxiety disorder, immunoregulation, neuroendocrine

Abstract

Anxiety disorder resulting from the interaction of psychological factors-caused anxiety and mood disorder symptoms is one of the clinical mental diseases. Excessive worry, nervousness and fear often bring about several negative outcomes, and seriously impact the physical, mental, and social functioning of patients. What’s worse, with poor treatment, anxiety disorder may develop into mental illnesses such as depression and schizophrenia. The treatment of anxiety has mainly recourse to drug therapy and psychotherapy; however, Western drug therapy represented by 5-hydroxytryptamine reuptake inhibitor often causes evident adverse effects, including nausea and constipation, as well as poor long-term medication compliance of patients. Citri Sarcodactylis Fructus can sooth the liver and regulate qi, which can be applied to alleviate anxiety disorder as an ancillary drug. Modern pharmacological research revealed that bergamot volatile oil, also known as bergamot essential oil (BEO), is the main active chemical component of Citri Sarcodactylis Fructus for anti-anxiety. BEO has been confirmed to exert an anti-anxiety effect through modulating neuronendocrine-immune network, including immunoregulation, suppression of hyperactive hypothalamic-pituitary-adrenal (HPA) axis, enhancement of function of hypothalamic-pituitary-thyroid (HPT) axis, modulation of neurotransmitter, and promotion of neurotrophic effect. The study discusses the current research status regarding the application of Citri Sarcodactylis Fructus for anti-anxiety in recent years, and deeply probes into the mechanism of Citri Sarcodactylis Fructus playing an anti-anxiety role via neuronendocrine-immune network, in an effort to provide references to clinical treatment of anxiety disorder and new ideas for developing drugs targeting anxiety disorders.

References

Li MJ, Ye TY, Qi DM, et al. Research Status of Clinical Trials of Drugs and Interventions for Anxiety Disorders. Chinese General Practice 2021; 24(11): 1418-1425.

Bai B, Li Y, Gai YL. Analysis of Clinical Effect of Psychological Nursing on Patients with Anxiety Disorder. Psychological Monthly 2022; 17(02): 144-145,186.

Bandelow B. Current and Novel Psychopharmacological Drugs for Anxiety Disorders. Advances in experimental medicine and biology 2020; 1191: 347-365.

Hu J, Teng J, Wang W, et al. Clinical efficacy and safety of traditional Chinese medicine Xiao Yao San in insomnia combined with anxiety. Medicine (Baltimore) 2021; 100(43): 27608.

Ma K, Wang X, Feng S, et al. From the perspective of Traditional Chinese Medicine: Treatment of mental disorders in COVID-19 survivors. Biomed Pharmacother 2020; 132: 110810.

Cao R, Hao EW, Du ZC, et al. Ingredients, Pharmacological Activities and Predictive Analysis of Q-markers of Guangfoshou (Citri Sarcodactylis Fructus). Chinese Archives of Traditional Chinese Medicine 2022; 40(09): 135-145,277.

Wai W, Joe C, Huang HZ. The efficacy of Bergamot Essential Oil Inhalation on Alleviation of Stress and Anxiety and Enhancement of Positive Effect: A Randomized Controlled Trial. The University of Hong Kong: Pokfulam, Hong Kong, China, 2021.

Hung CL, Lin YL, Chou CM, et al. Efficacy of Aromatherapy at Relieving the Work-Related Stress of Nursing Staff from Various Hospital Departments during COVID-19. Healthcare (Basel) 2023; 11(2): 157.

Wang YYZ. The Clinical Study of Inhalation Aromatherapy on Postoperative Anxiety and Pain in Patients with Laparoscopic Cholecystectomy. Lanzhou University: Lanzhou, China, 2018.

Pasyar N, Rambod M, Araghi F. The Effect of Bergamot Orange Essence on Anxiety, Salivary Cortisol, and Alpha Amylase in Patients Prior to Laparoscopic Cholecystectomy: A Controlled Trial Study. Complementary Therapies in Clinical Practice 2020; 39: 101153.

Qi Y. The Effect of The Method of Emotional Management Includes Citri Sarcodactylis Fructus and Cyperi Rhizoma combined aromatherapy accompanied with Horn tune music appreciation and Baduanjin (eight brocades) exercise in Patients with Hyperplasia of Mammary Glands and Anxiety. Zhejiang Chinese Medical University: Hangzhou, China, 2020.

Scuteri D, Rombolà L, Morrone LA, et al. Neuropharmacology of the Neuropsychiatric Symptoms of Dementia and Role of Pain: Essential Oil of Bergamot as a Novel Therapeutic Approach. International Journal of Molecular Sciences 2019; 20(13): 3327-3327.

Saiyudthong S, Marsden CA. Acute effects of bergamot oil on anxiety-related behaviour and corticosterone level in rats. Phytotherapy Research 2011; 25(6): 858-862.

Wakui N, Togawa C, Ichikawa K, et al. Relieving psychological stress and improving sleep quality by bergamot essential oil use before bedtime and upon awakening: A randomized crossover trial. Complementary Therapies in Medicine 2023; 77: 102976.

Rombolà L, Tridico L, Scuteri D, et al. Bergamot Essential Oil Attenuates Anxiety-Like Behaviour in Rats. Molecules 2017; 22(4): 614.

Watanabe E, Kuchta K, Kimura M, et al. Effects of bergamot (Citrus bergamia (Risso) Wright & Arn.) essential oil aromatherapy on mood states, parasympathetic nervous system activity, and salivary cortisol levels in 41 healthy females. Forschende Komplementärmedizin 2015; 22(1): 43-49.

Perna S, Spadaccini D, Botteri L, et al. Efficacy of Bergamot: From Anti-inflammatory and Anti-oxidative Mechanisms to Clinical Applications as Preventive Agent for Cardiovascular Morbidity, Skin Diseases, and Mood Alterations. Food Science & Nutrition 2019; 7(2): 369-384.

Zhang P, Zhang JQ, Li B, et al. Research Progress on Chemical Constituents and Pharmacological Effects of Bergamot Essential Oil. Chinese Traditional Patent Medicine 2023; 45(02): 514-518.

Li CY, Yuan Z, She CJ, et al. Research Progress on Chemical Constituents and Pharmacological Actions of Citri Sarcodactylis Fructus. Food and Drug 2022; 24(02): 187-193.

Zhou XQ. Analytic Research Progress on Chemical Compositions of the Volatile Oil of Bergamot. Shandong Chemical Industry 2022; 51(20): 103-105.

Scuteri D, Rombolà L, Crudo M, et al. Preclinical Characterization of Antinociceptive Effect of Bergamot Essential Oil and of Its Fractions for Rational Translation in Complementary Therapy. Pharmaceutics 2022; 14(2): 312.

Sun XH. Research on Extraction, Nanoemulsion and Biological Activities of Jinhua Fingered Citron Essential Oil. Journal of Jiangnan University: Wuxi, China, 2018.

Jin X, Xu X, Ding Q, et al. To Explore the Potential Molecular Mechanism of Complex Rose-Bergamot Essential Oil on Anti-anxiety with Facial Spots based on Network Pharmacology. Journal of Cosmetic Dermatology 2022; 21(11): 6363-6376.

Perri MR, Pellegrino M, Aquaro S, et al. Cachrys spp. from Southern Italy: Phytochemical Characterization and JAK/STAT Signaling Pathway Inhibition. Plants (Basel) 2022; 11(21): 2913.

Uzunova G, Pallanti S, Hollander E. Presentation and Management of Anxiety in Individuals with Acute Symptomatic or Asymptomatic COVID-19 Infection, and in the Post-COVID-19 Recovery Phase. International Journal of Psychiatry in Clinical Practice 2021; 25(2): 11-17.

Wang XL, Wu S, Wu Q, et al. Effects of Paeoniflorin on Anxiety-like Behavior, Inflammatory Factors and Intestinal Microflora in Alcohol Withdrawal Rats. Science and Technology of Food Industry 2022; 43(10): 378-387.

Deng YF, Guo KK, He RD, et al. Analysis of the correlation between the changes of serum inflammatory cytokines IL-1 alpha, IL-6, IL-12, CRP and the onset of generalized anxiety disorder and its mechanism analysis. Journal of International Psychiatry 2019; 46(01): 60-62.

Zhu Z, Jiang YS, Wei LG. The Change and Clinical Significance of IL-1β, IL-6 and IL-10 in Serum of Patients with Anxiety Disorder. Journal of International Psychiatry 2019; 46(03): 425-427,434.

Li LY, Zhao HW, Qi DM, et al. The Role of Neuroendocrine Immunomodulatory Network in the Pathogenesis of Anxiety Disorders. Journal of Psychiatry 2022; 35(02): 207-211.

Trombetta D, Cimino F, Cristani M, et al. In vitro Protective Effects of Two Extracts from Bergamot Peels on Human Endothelial Cells Exposed to Tumor Necrosis Factor-alpha (TNF-alpha). Journal of Agricultural and Food Chemistry 2010; 58(14): 8430-8436.

Risitano R, Currò M, Cirmi S, et al. Flavonoid Fraction of Bergamot Juice Reduces LPS-induced Inflammatory Response through SIRT1-mediated NF-κB Inhibition in THP-1 Monocytes. PloS One 2014; 9(9): e107431.

Gao S, Zou X, Wang Z, et al. Bergapten Attenuates Microglia-mediated Neuroinflammation and Ischemic Brain Injury by Targeting Kv1.3 and Carbonyl reductase 1. European Journal of Pharmacology 2022; 933: 175242.

Lombardo GE , Cirmi S , Musumeci L, et al. Mechanisms Underlying the Anti-Inflammatory Activity of Bergamot Essential Oil and Its Antinociceptive Effects. Plants 2020; 9(6): 704.

Cui Y, Che Y, Wang H. Bergamot Esential Oil Attenuate Aluminum-induced Anxiety-like Behavior through Antioxidation, Anti-inflammatory and GABA Regulation in Rats. Food and Chemical Toxicology 2020; 145: 111766.

Impellizzeri D, Bruschetta G, Paola RD, et al. The Anti-inflammatory and Antioxidant Effects of Bergamot Juice Extract (BJe) in an Experimental Model of Inflammatory Bowel Disease. Clinical Nutrition 2015, 34(6): 1146-1154.

Impellizzeri D, Cordaro M, Campolo M, et al. Anti-inflammatory and Antioxidant Effects of Flavonoid-rich Draction of Bergamot Juice (BJe) in a Mouse Model of Intestinal Ischemia/Reperfusion Injury. Frontiers in Pharmacology 2016; 7: 203.

Zhou SM, Liu HJ, Zhao RX, et al. Effect of Acupuncture Combined with Music Therapy on Behavior and T Lymphocyte Subsets in Anxiety Disorder Model Rats. Journal of Clinical Acupuncture and Moxibustion 2017; 33(03): 57-61.

Fang KQ. The Function and Regulation Mechanism of Purine-metabolic Disorder in T lymphocytes in the Onset of Anxiety. Zhejiang University: Hangzhou, China, 2020.

Bao XH, Ye TY, Qi DM, et al. Suanzaoren Tang and Its Modified Formulas on Prevention and Treatment of Anxiety Disorders: A Review. Chinese Journal of Experimental Traditional Medical Formulae 2022; 28(06): 237-245.

Song MQ, Feng ML, Ma L, et al. Effect of Citron and Bergamot on T cell Subsets in Depressed Rats. Shanxi Journal of Traditional Chinese Medicine 2015; 31(11): 54-56.

Huang Y. Clinical Study on Auricular Point Application Combined with Relaxation Training for Anxiety. Journal of New Chinese Medicine 2022; 54(04): 147-150.

Shen TZ, Pan JL, Jiang DD, et al. Betulinic Acid Attenuates Anxiety-like Behavior and Oxidative Stress in Mice. Chronic Pathematology Journal 2022; 23(03): 377-380,384.

Chen X. Effects of Electroacupuncture on SOD, MDA and CAT in Multiple Organs of Diabetic Rats. Chengdu Sport University: Chengdu, China, 2022.

Lu Y. Effects of Dingxin Decoction Combined with Western Medicine on Oxidative Stress, Neurotransmitters and Cytokines in Patients with Generalized Anxiety and Qi-Yin Deficiency Syndrome. Journal of New Chinese Medicine 2022; 54(19): 64-70.

Zhen LF, Zhu LL, Yang Z, et al. Clinical Study on Jiuwei Zhenxin Granules Assisting Sertraline Hydrochloride for Generalized Anxiety Disorder. Journal of New Chinese Medicine 2021; 53(19): 74-77.

Shao LX. Effects of the Extract from Bergamot and Boxthorn on the Delay of Skin Aging and Hair Growth in Mice. China Journal of Chinese Materia Medica 2003; (08): 77-80.

Wang L. Study on the Effect Mechanism of Fermented Citri Sarcodactylis Fructus Extract on the Improvement of Disordered Glycolipid Metabolic Mice. Guangdong Pharmaceutical University: Guangzhou, China, 2021.

Mollace R, Macrì R, Tavernese A, et al. Comparative Effect of Bergamot Polyphenolic Fraction and Red Yeast Rice Extract in Rats Fed a Hyperlipidemic Diet: Role of Antioxidant Properties and PCSK9 Expression. Nutrients 2022; 14(3): 477-477.

Dounousi E, Tellis C, Pavlakou P, et al. Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients. Oxidative Medicine and Cellular Longevity 2021; 2021: 6677012-6677012.

Barisione C, Verzola D, Garibaldi S, et al. Renal Ischemia/Reperfusion Early Induces Myostatin and PCSK9 Expression in Rat Kidneys and HK-2 Cells. International Journal of Molecular Sciences 2021; 22(18): 9884.

Xu LS, Jin XL. Effect of the Ethanolic Extract of Jinhua Bergamot on Learning Memory of Mice. Special Wild Economic Animal and Plant Research 2002; 2002(04): 16-18.

Huang JC, Xie W, Deng N, et al. Foshouningshen Decoction Improves Sleeping via the Serotonergic System in a Rat Model of Insomnia. Journal of Southern Medical University 2017; 37(08): 1116-1120.

Rombolà L, Scuteri D, Watanabe C, et al. Role of 5-HT1A Receptor in the Anxiolytic-Relaxant Effects of Bergamot Essential Oil in Rodent. International Journal of Molecular Sciences 2020; 21(7): 2597-2597.

Zhuang X. Impacts of IL-33 in the Amygdala upon Anxiety and Its Molecular Mechanism. Shandong University: Jinan, China, 2021.

Jiang ZK, Ning EJ, Wang XF, et al. Anti-anxiety Effect of Platycladi Semen and Related Mechanism. Zhongnan Pharmacy 2021; 19(12): 2540-2544.

Rombolà L, Scuteri D, Adornetto A, et al. Anxiolytic-Like Effects of Bergamot Essential Oil Are Insensitive to Flumazenil in Rats. Evidence-based Complementary and Alternative Medicine: eCAM 2019; 2019: 2156873.

Amantea D, Fratto V, Maida S, et al. Chapter 27 Prevention of Glutamate Accumulation and Upregulation of Phospho-Akt may Account for Neuroprotection Afforded by Bergamot Essential Oil against Brain Injury Induced by Focal Cerebral Ischemia in Rat. International Review of Neurobiology 2009; 85: 389-405.

Morrone LA, Rombolà L, Pelle C, et al. The essential oil of bergamot enhances the levels of amino acid neurotransmitters in the hippocampus of rat: implication of monoterpene hydrocarbons. Pharmacological Research 2007; 55(4): 255-262.

Wang CN, Jiang C, Wang H, et al. To Explore the Mechanism of Anti-depression Effect of Cherry Leaf Decoction on CUMS Rats based on BDNF Pathway. Traditional Chinese Drug Research and Clinical Pharmacology 2022; 33(03): 342-348.

Xie XY. Discussion on the Anti-anxiety Effect of Regulating Spirit Acupuncture Technique based on the HPA Axis Neuromodulation: A Clinical and Mechanism Research. Guangzhou University of Traditional Chinese Medicine: Guangzhou, China, 2021.

Li YM, Li D, Zhang P, et al. Study on the Correlation of Serum Peroxidoreductase 1 and Brain-derived Neurotrophic Factor with Symptoms of Depression and Anxiety in Patients with Irritable Bowel Syndrome. Journal of Clinical and Experimental Medicine 2022; 21(04): 364-367.

Gao HY, Tian Q. Antidepressant Effect of Fingered Citron Volatile in Rats. Chinese Journal of Experimental Traditional Medical Formulae 2012; 18(07): 231-234.

Saiyudthong S, Mekseepralard C. Effect of Inhaling Bergamot Oil on Depression-Related Behaviors in Chronic Stressed Rats. Journal of the Medical Association of Thailand 2015; 98: 152-159.

Xiao QQ, Gao J, He LC, et al. Effect of Tianwang Buxin Pills on HPA-related Hormones and Receptor Genes Expression in Rats with Generalized Anxiety Disorder of Heart Yin Deficiency. Liaoning Journal of Traditional Chinese Medicine 2019; 46(06): 1137-1142.

Yang H, Zhou AM, Lin MH, et al. Research Progress of Extraction Methods and Pharmacological Effects of Bergamot Essential Oil. Journal of Food Safety & Quality 2013; 4(05): 1347-1352.

Chen ZB, Zhang B, Liu XM, et al. Research Progress on the Pathogenesis of Anxiety. Tianjin Journal of Traditional Chinese Medicine 2018; 35(04): 316-320.

Song MQ, Ma L, Jia LL, et al. Effects of Couplet Medicines Citron Fruit and Finger Citron on HPT-HPA Axis in CUMS Rats. China Journal of Traditional Chinese Medicine and Pharmacy 2017; 32(10): 4633-4636.