Login Register Cart 0
Generic placeholder image

Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Evaluation of the Antidepressant-like Effect of Total Sterols Fraction and Stigmasterol Isolated from Leaves of Aegle marmelos and Possible Mechanism( s) of Action Involved

Author(s): Sourav Ghosh*, Arvind Kumar, Neetu Sachan and Phool Chandra

Volume 19, Issue 2, 2022

Published on: 29 July, 2021

Article ID: e290721195144 Pages: 15

DOI: 10.2174/1570163818666210729165310

Price: $65

Abstract

Background: Aegle marmelos Corr. (Rutaceae) commonly known as ‘Indian Bael’ has been used as a brain tonic traditionally. However, despite this traditional use, not enough scientific report is present that can confirm the use of this plant in neurological disorders. Thus, the total sterols fraction and stigmasterol from the leaves of Aegle marmelos were investigated for antidepressant-like effect along with their possible mechanism(s) of action by primarily performing acute toxicity study of total sterols.

Methods: An acute toxicological study was carried out at a single oral dose of 2000 mg/kg. Sign of toxicity was observed by estimating biochemical and performing histopathological analysis. For the antidepressant-like effect, different doses of total sterols (50-200 mg/kg, p.o. for seven days) and stigmasterol (5- 20 mg/kg, i.p. acute) were administered in mice using TST and FST models. To evaluate the mechanism of action, mice were pretreated with GABA, 5-HT, DA, adrenergic antagonists, and glutamate agonists. Furthermore, a neurochemical study was performed following TST and molecular docking study was also performed to determine the binding affinity of stigmasterol.

Results: Total sterols fraction presents no sign of toxicity up to the oral dose of 2000 mg/kg. Oral treatment of total sterols and acute intraperitoneal treatment of stigmasterol (except 5 mg/kg) reduced the immobility time significantly. Pretreatment with pCPA (5-HT synthesis inhibitor) and NMDA (an agonist of the glutamate site) effectively reversed the immobility time of total sterols and stigmasterol (except pCPA) in TST. However, bicuculline (competitive GABA antagonist), haloperidol (D2 dopaminergic antagonist) and prazosin (α1 adrenergic antagonist) could not reverse the immobility time. Meanwhile, total sterols also effectively altered the hippocampus 5-HT and Glu levels. Also, the result of the molecular docking study depicted that stigmasterol has an affinity to the NMDA receptor.

Conclusions: The present study suggests that the total sterols fraction did not produce any acute toxicity in rats. Also, we reported that total sterols, stigmasterol and sub-effective stigmasterol coadministration with fluoxetine significantly reduced the time of immobility in TST and FST confirmed the antidepressant-like effect of total sterols fraction and stigmasterol. Moreover, further findings suggest that the antidepressant-like effect of total sterols might be mediated by the serotonergic and glutamatergic systems. Whereas only the glutamatergic system was involved in the antidepressant activity of stigmasterol.

Keywords: Aegle marmelos, phytosterols, antidepressant-like effect, serotonergic system, glutamatergic system, stigmasterol.

Graphical Abstract

[1]
Girish C, Raj V, Arya J, Balakrishnan S. Evidence for the involvement of the monoaminergic system, but not the opioid system in the antidepressant-like activity of ellagic acid in mice. Eur J Pharmacol 2012; 682(1-3): 118-25.
[http://dx.doi.org/10.1016/j.ejphar.2012.02.034] [PMID: 22387858]
[2]
Ge JF, Gao WC, Cheng WM, et al. Orcinol glucoside produces antidepressant effects by blocking the behavioural and neuronal deficits caused by chronic stress. Euro Neuropsychopharmacol: J Euro Coll Neuropsychopharmacol 2014; 24: 172-80.
[http://dx.doi.org/10.1016/j.euroneuro.2013.05.007]
[3]
Hasler G. Pathophysiology of depression: Do we have any solid evidence of interest to clinicians? World Psychiatry 2010; 9(3): 155-61.
[http://dx.doi.org/10.1002/j.2051-5545.2010.tb00298.x] [PMID: 20975857]
[4]
Lang UE, Borgwardt S. Molecular mechanisms of depression: Perspectives on new treatment strategies. Cell Physiol Biochem 2013; 31: 761-77.
[http://dx.doi.org/10.1159/000350094]
[5]
Pesarico AP, Sampaio TB, Stangherlin EC, Mantovani AC, Zeni G, Nogueira CW. The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems. Prog Neuropsychopharmacol Biol Psychiatry 2014; 54: 179-86.
[http://dx.doi.org/10.1016/j.pnpbp.2014.06.001] [PMID: 24936772]
[6]
Poleszak E, Wlaź P, Szewczyk B, et al. A complex interaction between glycine/NMDA receptors and serotonergic/noradrenergic antidepressants in the forced swim test in mice. J Neural Transm (Vienna, Austria : 1996) 2011; 118: 1535-46.
[7]
Ghosh S, Kumar A, Sachan N, Chandra P. Bioactive compounds and distinctive pharmacological activity guided review of Aegle marmelos: A miraculous plant of indigenous medicine system. CBC 2020; 16: 965-77.
[http://dx.doi.org/10.2174/1573407215666191101091412]
[8]
Maheshwari JK, Singh JP. Plants used in ethnomedicine by the Kols of Allahabad district Uttar Pradesh. J Bulletin of Medico-Ethno-Botanical Reserch 1984; 5: 105-21.
[9]
Yang C, Yu L, Li W, Xu F, Cohen JC, Hobbs HH. Disruption of cholesterol homeostasis by plant sterols. J Clin Invest 2004; 114(6): 813-22.
[http://dx.doi.org/10.1172/JCI22186] [PMID: 15372105]
[10]
Awad AB, Fink CS. Phytosterols as anticancer dietary components: Evidence and mechanism of action. J Nutr 2000; 130(9): 2127-30.
[http://dx.doi.org/10.1093/jn/130.9.2127] [PMID: 10958802]
[11]
Bouic PJ. The role of phytosterols and phytosterolins in immune modulation: A review of the past 10 years. Curr Opin Clin Nutr Metab Care 2001; 4(6): 471-5.
[http://dx.doi.org/10.1097/00075197-200111000-00001] [PMID: 11706278]
[12]
Vanmierlo T, Weingärtner O, van der Pol S, et al. Dietary intake of plant sterols stably increases plant sterol levels in the murine brain. J Lipid Res 2012; 53(4): 726-35.
[http://dx.doi.org/10.1194/jlr.M017244] [PMID: 22279184]
[13]
Zhen XH, Quan YC, Jiang HY, Wen ZS, Qu YL, Guan LP. Fucosterol, a sterol extracted from Sargassum fusiforme, shows antidepressant and anticonvulsant effects. Eur J Pharmacol 2015; 768: 131-8.
[http://dx.doi.org/10.1016/j.ejphar.2015.10.041] [PMID: 26515446]
[14]
Gürağaç Dereli FT, Ilhan M, Küpeli Akkol E. Identification of the main active antidepressant constituents in a traditional Turkish medicinal plant, Centaurea kurdica Reichardt. J Ethnopharmacol 2020; 249112373
[http://dx.doi.org/10.1016/j.jep.2019.112373] [PMID: 31689479]
[15]
Zhao D, Zheng L, Qi L, et al. Structural features and potent antidepressant effects of total sterols and β-sitosterol extracted from sargassum horneri. Mar Drugs 2016; 14(7): 14.
[http://dx.doi.org/10.3390/md14070123] [PMID: 27367705]
[16]
Herborne JB. Phytochemical methods. A guide to modern techniques of plant analysis. J Ethnopharmacol 2015; 23: 200-13.
[17]
Xu WL, Huang YB, Qian JH, et al. Separation and purification of stigmasterol and β-sitosterol from phytosterol mixtures by solvent crystallization method. Separ Purif Tech 2005; 41: 173-8.
[http://dx.doi.org/10.1016/j.seppur.2004.02.005]
[18]
Diniz TC, de Oliveira Júnior RG, Miranda Bezerra Medeiros MA, et al. Anticonvulsant, sedative, anxiolytic and antidepressant activities of the essential oil of Annona vepretorum in mice: Involvement of GABAergic and serotonergic systems. Biomed Pharmacother 2019; 111: 1074-87.
[19]
Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: A primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977; 229(2): 327-36.
[PMID: 596982]
[20]
Yan T, Xu M, Wu B, et al. The effect of Schisandra chinensis extracts on depression by noradrenergic, dopaminergic, GABAergic and glutamatergic systems in the forced swim test in mice. Food Funct 2016; 7(6): 2811-9.
[http://dx.doi.org/10.1039/C6FO00328A] [PMID: 27225351]
[21]
Cryan JF, Mombereau C, Vassout A. The tail suspension test as a model for assessing antidepressant activity: Review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev 2005; 29(4-5): 571-625.
[http://dx.doi.org/10.1016/j.neubiorev.2005.03.009] [PMID: 15890404]
[22]
Zhang T, Du Y, Liu X, et al. Study on antidepressant-like effect of protoilludane sesquiterpenoid aromatic esters from Armillaria Mellea. Nat Prod Res 2021; 35(6): 1042-5.
[http://dx.doi.org/10.1080/14786419.2019.1614577] [PMID: 31135223]
[23]
O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open babel: An open chemical toolbox. J Cheminform 2011; 3: 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[24]
Kumar G, Patnaik R. Exploring neuroprotective potential of Withania somnifera phytochemicals by inhibition of GluN2B-containing NMDA receptors: An in silico study. Med Hypotheses 2016; 92: 35-43.
[http://dx.doi.org/10.1016/j.mehy.2016.04.034] [PMID: 27241252]
[25]
Laskowski RA, Swindells MB. LigPlot+: Multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 2011; 51(10): 2778-86.
[http://dx.doi.org/10.1021/ci200227u] [PMID: 21919503]
[26]
Ghosh T, Maity TK, Singh J. Evaluation of antitumor activity of stigmasterol, a constituent isolated from Bacopa monnieri Linn aerial parts against Ehrlich Ascites Carcinoma in mice. Orient Pharm Exp Med 2011; 11: 41-9.
[http://dx.doi.org/10.1007/s13596-011-0001-y]
[27]
Alam MS, Chopra N, Ali M, Niwa M. Oleanen and stigmasterol derivatives from Ambroma augusta. Phytochemistry 1996; 41: 1197-200.
[http://dx.doi.org/10.1016/0031-9422(95)00774-1]
[28]
Bonomini TJ, Holzmann I, Thiesen LC, et al. Neuropharmacological and acute toxicological evaluation of ethanolic extract of Allamanda cathartica L. flowers and plumieride. Regul Toxicol Pharmacol 2017; 91: 9-19.
[http://dx.doi.org/10.1016/j.yrtph.2017.10.005] [PMID: 28986178]
[29]
Olorunnisola OS, Bradley G, Afolayan AJ. Acute and sub-chronic toxicity studies of methanolic extract of Tulbaghia violacea rhizomes in Wistar rats. Afr J Biotechnol 2012; 11: 14934-40.
[30]
Brautbar N, Williams JII. Industrial solvents and liver toxicity: Risk assessment, risk factors and mechanisms. Int J Hyg Environ Health 2002; 205(6): 479-91.
[http://dx.doi.org/10.1078/1438-4639-00175] [PMID: 12455270]
[31]
Cabral CE, Klein MRST. Phytosterols in the treatment of hypercholesterolemia and prevention of cardiovascular diseases. Arq Bras Cardiol 2017; 109(5): 475-82.
[http://dx.doi.org/10.5935/abc.20170158] [PMID: 29267628]
[32]
Davis ME, Berndt WD. Renal methods for toxicologyPrinciples methods of toxicology 3rd. New York: Raven 1994; pp. 871-94.
[33]
Olson H, Betton G, Robinson D, et al. Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharmacol 2000; 32(1): 56-67.
[http://dx.doi.org/10.1006/rtph.2000.1399] [PMID: 11029269]
[34]
Slichter SJ. Relationship between platelet count and bleeding risk in thrombocytopenic patients. Transfus Med Rev 2004; 18(3): 153-67.
[http://dx.doi.org/10.1016/j.tmrv.2004.03.003] [PMID: 15248165]
[35]
Schortgen F, Lacherade JC, Bruneel F, et al. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: A multicentre randomised study. Lancet 2001; 357(9260): 911-6.
[http://dx.doi.org/10.1016/S0140-6736(00)04211-2] [PMID: 11289347]
[36]
Krishnan V, Nestler EJ. Animal models of depression: Molecular perspectives. Curr Top Behav Neurosci 2011; 7: 121-47.
[http://dx.doi.org/10.1007/7854_2010_108] [PMID: 21225412]
[37]
Kwon S, Lee B, Kim M, Lee H, Park HJ, Hahm DH. Antidepressant-like effect of the methanolic extract from Bupleurum falcatum in the tail suspension test. Prog Neuropsychopharmacol Biol Psychiatry 2010; 34(2): 265-70.
[http://dx.doi.org/10.1016/j.pnpbp.2009.11.015] [PMID: 19932727]
[38]
Kothari S, Minda M, Tonpay SD. Anxiolytic and antidepressant activities of methanol extract of Aegle marmelos leaves in mice. Indian J Physiol Pharmacol 2010; 54(4): 318-28.
[PMID: 21675029]
[39]
McCormick DA. GABA as an inhibitory neurotransmitter in human cerebral cortex. J Neurophysiol 1989; 62(5): 1018-27.
[http://dx.doi.org/10.1152/jn.1989.62.5.1018] [PMID: 2573696]
[40]
Grønli J, Fiske E, Murison R, et al. Extracellular levels of serotonin and GABA in the hippocampus after chronic mild stress in rats. A microdialysis study in an animal model of depression. Behav Brain Res 2007; 181(1): 42-51.
[http://dx.doi.org/10.1016/j.bbr.2007.03.018] [PMID: 17477980]
[41]
Goldberg JF, Burdick KE. Cognitive side effects of anticonvulsants. J Clin Psychiatry 2001; 62(Suppl. 14): 27-33.
[PMID: 11469672]
[42]
Möhler H. The GABA system in anxiety and depression and its therapeutic potential. Neuropharmacology 2012; 62(1): 42-53.
[http://dx.doi.org/10.1016/j.neuropharm.2011.08.040] [PMID: 21889518]
[43]
Pinto Brod LM, Fronza MG, Vargas JP, et al. Involvement of monoaminergic system in the antidepressant-like effect of (octylseleno)-xylofuranoside in the mouse tail suspension test. Prog Neuropsychopharmacol Biol Psychiatry 2016; 65: 201-7.
[http://dx.doi.org/10.1016/j.pnpbp.2015.10.008] [PMID: 26596986]
[44]
Machado-Vieira R, Manji HK, Zarate CA. The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist 2009; 15(5): 525-39.
[http://dx.doi.org/10.1177/1073858409336093] [PMID: 19471044]
[45]
Pochwat B, Pałucha-Poniewiera A, Szewczyk B, Pilc A, Nowak G. NMDA antagonists under investigation for the treatment of major depressive disorder. Expert Opin Investig Drugs 2014; 23(9): 1181-92.
[http://dx.doi.org/10.1517/13543784.2014.918951] [PMID: 24818801]
[46]
Musazzi L, Treccani G, Mallei A, Popoli M. The action of antidepressants on the glutamate system: Regulation of glutamate release and glutamate receptors. Biol Psychiatry 2013; 73(12): 1180-8.
[http://dx.doi.org/10.1016/j.biopsych.2012.11.009] [PMID: 23273725]
[47]
de Ruyck J, Brysbaert G, Blossey R, Lensink MF. Molecular docking as a popular tool in drug design, an in silico travel. Adv Appl Bioinform Chem 2016; 9: 1-11.
[http://dx.doi.org/10.2147/AABC.S105289] [PMID: 27390530]

Rights & Permissions Print Cite
Article Metrics
28
1
© 2024 Bentham Science Publishers | Privacy Policy