Abstract
Depression is a debilitating mood disorder affecting millions worldwide and continues to pose a significant global health burden. Due to the multifaceted nature of depression, the current treatment regimens are not up to mark in terms of their multitargeting potential and least side effect profile. Molecules within the isoflavone class demonstrate promising potential in alleviating depression and associated conditions, offering a multifaceted approach to manage mental health concerns. Therefore, the current study was designed to explore the potential of glycitein, an isoflavone in managing reserpine-induced depression and associated comorbidities in mice. Reserpine (0.5 mg/kg; i.p.) administration for the first 3 days induced depression and associated comorbidities as evidenced by increased immobility time in forced swim test (FST) and tail suspension test (TST), along with reduced locomotor activity in the open field test (OFT) and increased latency to reach the platform in the Morris water maze (MWM) test. Reserpine treatment also upregulated and downregulated the brain thiobarbituric acid reactive substance (TBARS) and glutathione (GSH) levels, respectively. Furthermore, reserpine administration also uplifted the level of TNF-α in the serum samples. Glycitein (3 mg/kg and 6 mg/kg; p.o.) treatment for 5 days prevented the depressive effect of reserpine. It also improved the spatial memory at both dose levels. Moreover, in biochemical analysis, glycitein also reduced the brain TBARS and serum tumor necrosis factor-alpha (TNF-α) levels. Whereas, no significant effect was seen on the brain GSH level. Glycitein (6 mg/kg) was found to be more effective than the 3 mg/kg dose of glycitein. Overall results delineate that glycitein has the potential to manage depression and impaired memory by inhibiting lipid peroxidation and inflammatory stress.
Similar content being viewed by others
Data availability
The data that support the findings of this study are available from the corresponding author upon request.
References
Almeida SS, Zizzi FB, Cattaneo A, Comandini A, Di Dato G, Lubrano E, Pellicano C, Spallone V, Tongiani S, Torta R (2020) Management and treatment of patients with major depressive disorder and chronic diseases: a multidisciplinary approach. Front Psychol 11:542444
Arias JA, Williams C, Raghvani R, Aghajani M, Baez S, Belzung C, Booij L, Busatto G, Chiarella J, Fu CH, Ibanez A (2020) The neuroscience of sadness: a multidisciplinary synthesis and collaborative review. Neurosci Biobehav Rev 111:199–228
Arora V, Chopra K (2013) Possible involvement of oxide-nitrosative stress induced neuro-inflammatory cascade and monoaminergic pathway: underpinning the correlation between nociceptive and depressive behavior in a rodent model. J Affect Disord 151:1041–1052
Bajpai A, Verma AK, Srivastava M, Srivastava R (2014) Oxidative stress and major depression. J Clin Diagn Res JCDR 8(12):CC04
Ballenger JC (2000) Anxiety and depression: optimizing treatments. Prim Care Companion J Clin Psychiatry 2(3):71
Bhatt S, Nagappa AN, Patil CR (2020) Role of oxidative stress in depression. Drug Discov Today 25(7):1270–1276
Black CN, Bot M, Scheffer PG, Cuijpers P, Penninx BW (2015) Is depression associated with increased oxidative stress? A systematic review and meta-analysis. Psychoneuroendocrinology 51:164–175
Brandeis R, Brandys Y, Yehuda S (1989) The use of the Morris water maze in the study of memory and learning. Int J Neurosci 48(1–2):29–69
Brigitta B (2002) Pathophysiology of depression and mechanisms of treatment. Dialogues Clin Neurosci 4(1):7–20
Chen L, Wang X, Zhang Y, Zhong H, Wang C, Gao P, Li B (2021) Daidzein alleviates hypothalamic-pituitary-adrenal axis hyperactivity, ameliorates depression-like behavior, and partly rectifies circulating cytokine imbalance in two rodent models of depression. Front Behav Neurosci 15:671864
Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503
Correia AS, Cardoso A, Vale N (2023) Oxidative stress in depression: the link with the stress response, neuroinflammation, serotonin, neurogenesis and synaptic plasticity. Antioxidants 12(2):470
Dantzer R, O’connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9(1):46–56
Dillon DG, Pizzagalli DA (2018) Mechanisms of memory disruption in depression. Trends Neurosci 41(3):137–149
Dobrek L, Głowacka K (2023) Depression and its phytopharmacotherapy—a narrative review. Int J Mol Sci 24(5):4772
Galkin SA, Peshkovskaya AG, Simutkin GG, Vasil’eva SN, Roshchina OV, Ivanova SA, Bokhan NA (2020) Impairments to the functions of spatial working memory in mild depression and their neurophysiological correlates. Neurosci Behav Physiol 50(7):825–829
Ghani MA, Barril C, Bedgood DR Jr, Prenzler PD (2017) Measurement of antioxidant activity with the thiobarbituric acid reactive substances assay. Food Chem 230:195–207
Gorman JM (1996) Comorbid depression and anxiety spectrum disorders. Depress Anxiety 4(4):160–168
Gutierrez-Zepeda A, Santell R, Wu Z, Brown M, Wu Y, Khan I, Link CD, Zhao B, Luo Y (2005) Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans. BMC Neurosci 6(1):54
Guven H, Arici A, Simsek O (2019) Flavonoids in our foods: a short review. J Basic Clin Health Sci 3(2):96–106
Hao Y, Ge H, Sun M, Gao Y (2019) Selecting an appropriate animal model of depression. Int J Mol Sci 20(19):4827
Hopwood M (2023) Anxiety symptoms in patients with major depressive disorder: commentary on prevalence and clinical implications. Neurol Ther 12:5–12
Hu P, Ma L, Wang YG, Ye F, Wang C, Zhou WH, Zhao X (2017) Genistein, a dietary soy isoflavone, exerts antidepressant-like effects in mice: involvement of serotonergic system. Neurochem Int 108:426–435
Ibrahim WH, Habib HM, Chow CK, Bruckner GG (2008) Isoflavone-rich soy isolate reduces lipid peroxidation in mouse liver. Int J Vitam Nutr Res 78(45):217–222
Ji N, Lei M, Chen Y, Tian S, Li C, Zhang B (2023) How oxidative stress induces depression. ASN Neuro 15:1–26
Kalin NH (2020) The critical relationship between anxiety and depression. Am J Psychiatry 177(5):365–367
Kang KA, Zhang R, Piao MJ, Lee KH, Kim BJ, Kim SY, Hyun JW (2007) Inhibitory effects of glycitein on hydrogen peroxide induced cell damage by scavenging reactive oxygen species and inhibiting c-Jun N-terminal kinase. Free Radical Res 41(6):720–729
Kenney MJ, Ganta CK (2014) Autonomic nervous system and immune system interactions. Compr Physiol 4(3):1177
Kim BC, Lim I, Ha J (2023) Metabolic profiling and expression analysis of key genetic factors in the biosynthetic pathways of antioxidant metabolites in mungbean sprouts. Front Plant Sci 14:1207940
Kim IS (2021) Current perspectives on the beneficial effects of soybean isoflavones and their metabolites for humans. Antioxidants 10(7):1064
Lee RS, Hermens DF, Porter MA, Redoblado-Hodge MA (2012) A meta-analysis of cognitive deficits in first-episode major depressive disorder. J Affect Disord 140(2):113–124
Liu SB, Zhao R, Li XS, Guo HJ, Tian Z, Zhang N, Gao GD, Zhao MG (2014) Attenuation of reserpine-induced pain/depression dyad by gentiopicroside through downregulation of GluN2B receptors in the amygdala of mice. NeuroMolecular Med 16:350–359
Lu C, Gao R, Zhang Y, Jiang N, Chen Y, Sun J, Wang Q, Fan B, Liu X, Wang F (2021) S-equol, a metabolite of dietary soy isoflavones, alleviates lipopolysaccharide-induced depressive-like behavior in mice by inhibiting neuroinflammation and enhancing synaptic plasticity. Food Funct 12(13):5770–5778
Lu C, Wei Z, Wang Y, Li S, Tong L, Liu X, Fan B, Wang F (2022) Soy isoflavones alleviate lipopolysaccharide-induced depressive-like behavior by suppressing neuroinflammation, mediating tryptophan metabolism and promoting synaptic plasticity. Food Funct 13(18):9513–9522
Morris RG (1981) Spatial localization does not require the presence of local cues. Learn Motiv 12(2):239–260
Porsolt RD, Le Pichon M, Jalfre ML (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266(5604):730–732
Probert L (2015) TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience 302:2–2
Qian X, Zhong Z, Lu S, Zhang Y (2023) Repeated reserpine treatment induces depressive-like behaviors accompanied with hippocampal impairment and synapse deficit in mice. Brain Res 1819:148541
Reiter R, Paredes S, Korkmaz A, Jou MJ, Tan DX (2008) Melatonin combats molecular terrorism at the mitochondrial level. Interdiscip Toxicol 1(2):137–149
Samad N, Khaliq S, Alam M, Yasmin F, Ahmad S, Mustafa S, Raza U (2021) Tryptophan lessens reserpine induced anxiety, depression and memory impairment by modulating oxidative stress and serotonergic activity. Pak J Pharm Sci 2:34
Samad N, Saleem A, Yasmin F, Shehzad MA (2018) Quercetin protects against stress-induced anxiety- and depression-like behavior and improves memory in male mice. Physiol Res 67(5):795–808
Singh G, Singh A, Singh P, Bhatti R (2019) Bergapten ameliorates vincristine-induced peripheral neuropathy by inhibition of inflammatory cytokines and NFκB signaling. ACS Chem Neurosci 10(6):3008–3017
Singh L, Kaur A, Garg S, Singh AP, Bhatti R (2020b) Protective effect of esculetin, natural coumarin in mice model of fibromyalgia: targeting pro-inflammatory cytokines and MAO-A. Neurochem Res 45:2364–2374
Singh S, Roy D, Sinha K, Parveen S, Sharma G, Joshi G (2020a) Impact of COVID-19 and lockdown on mental health of children and adolescents: a narrative review with recommendations. Psychiatry Res 293:113429
Song TT, Hendrich S, Murphy PA (1999) Estrogenic activity of glycitein, a soy isoflavone. J Agric Food Chem 47(4):1607–1610
Sousa FS, Birmann PT, Baldinotti R, Fronza MG, Balaguez R, Alves D, Brüning CA, Savegnago L (2018) α-(phenylselanyl) acetophenone mitigates reserpine-induced pain–depression dyad: Behavioral, biochemical and molecular docking evidences. Brain Res Bull 142:129–137
Steru L, Chermat R, Thierry B, Simon P (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology 85:367–370
Strawbridge R, Javed RR, Cave J, Jauhar S, Young AH (2023) The effects of reserpine on depression: a systematic review. J Psychopharmacol 37(3):248–260
Tian JS, Cui YL, Hu LM, Gao S, Chi W, Dong TJ, Liu LP (2010) Antidepressant-like effect of genipin in mice. Neurosci Lett 479(3):236–239
WHO (2021) Depressive disorder (depression). https://www.who.int/news-room/fact-sheets/detail/depression#:~:text=Women%20are%20more%20likely%20to,world%20have%20depression%20(1)
WHO (2023) COVID-19 pandemic triggers 25% increase in prevalence of anxiety and depression worldwide. https://www.who.int/news/item/02-03-2022-covid-19-pandemic-triggers-25-increase-in-prevalence-of-anxiety-and-depression-worldwide
Zhao X, Wang C, Cui WG, Ma Q, Zhou WH (2015) Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system. Sci Rep 5(1):9043
Zong Y, Chen T, Dong H, Zhu L, Ju W (2020) Si-Ni-San prevents reserpine-induced depression by inhibiting inflammation and regulating CYP450 enzymatic activity. Front Pharmacol 10:1518
Acknowledgements
The authors gratefully acknowledge the financial assistance provided by the University Institute of Pharma Sciences, Chandigarh University.
Author information
Authors and Affiliations
Contributions
Diksha performed all the experiments and wrote the manuscript. Lovedeep Singh conceptualized the study and also helped in writing the manuscript. Lovedeep Singh and Diksha revised the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
Corresponding author
Ethics declarations
Ethics approval
The entire animal study was approved by the Institutional Animal Ethics Committee on 4 Jan 2023 (approval no. CU/2022/IAEC/7/10). All the experiments were carried out by the Ministry of Environment and Forests’ ethical guidelines.
Consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Diksha, Singh, L. Glycitein prevents reserpine-induced depression and associated comorbidities in mice: modulation of lipid peroxidation and TNF-α levels. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03007-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00210-024-03007-9