Garcinia mangostana Linn displays antidepressant-like and pro-cognitive effects in a genetic animal model of depression: a bio-behavioral study in the Flinders Sensitive Line rat
There is abundant evidence for both disorganized redox balance and cognitive deficits in major depressive disorder (MDD). Garcinia mangostana Linn (GM) has anti-oxidant activity. We studied the antidepressant-like and pro-cognitive effects of raw GM rind in Flinders Sensitive Line (FSL) rats, a genetic model of depression, following acute and chronic treatment compared to a reference antidepressant, imipramine (IMI). The chemical composition of the GM extract was analysed for levels of α- and γ-mangostin. The acute dose-dependent effects of GM (50, 150 and 200 mg/kg po), IMI (20 mg/kg po) and vehicle were determined in the forced swim test (FST) in FSL rats, versus Flinders Resistant Line (FRL) control rats. Locomotor testing was conducted using the open field test (OFT). Using the most effective dose above coupled with behavioral testing in the FST and cognitive assessment in the novel object recognition test (nORT), a fixed dose 14-day treatment study of GM was performed and compared to IMI- (20 mg/kg/day) and vehicle-treated animals. Chronic treated animals were also assessed with respect to frontal cortex and hippocampal monoamine levels and accumulation of malondialdehyde. FSL rats showed significant cognitive deficits and depressive-like behavior, with disordered cortico-hippocampal 5-hydroxyindole acetic acid (5-HIAA) and noradrenaline (NA), as well as elevated hippocampal lipid peroxidation. Acute and chronic IMI treatment evoked pronounced antidepressant-like effects. Raw GM extract contained 117 mg/g and 11 mg/g α- and γ-mangostin, respectively, with acute GM demonstrating antidepressant-like effects at 50 mg/kg/day. Chronic GM (50 mg/kg/d) displayed significant antidepressant- and pro-cognitive effects, while demonstrating parity with IMI. Both behavioral and monoamine assessments suggest a more prominent serotonergic action for GM as opposed to a noradrenergic action for IMI, while both IMI and GM reversed hippocampal lipid peroxidation in FSL animals. Concluding, FSL rats present with cognitive deficits and depressive-like behaviors that are reversed by acute and chronic GM treatment, similar to that of IMI.
KeywordsEthnopharmacology Mangosteen Oxidative stress Inflammation Chromatographic fingerprinting Psychiatry
The authors would like to thank Hylton Bunting and Antoinette Fick for their assistance in the breeding and welfare of the animals. The authors would also like to thank Dr Dewet Wolmarans for assistance with analyzing the nORT data, Dr Makhotso Lekhooa for valuable insights into the writing of the paper, and Trent Ashton (Deakin University, Australia) for assisting with the chromatographic fingerprinting of GM. We also acknowledge Walter Dreyer and Francois Viljoen for their assistance during the ELISA and HPLC analyses, respectively.
Sources of funding
The authors declare that this work has been funded by the South African National Research Foundation (BHH; grant number 77323). The grant-holder acknowledges that opinions, findings and conclusions or recommendations expressed in any publication generated by NRF supported research are those of the authors, and that the NRF accepts no liability whatsoever in this regard. This funder had no other role in the study. MB is supported by a NHMRC Senior Principal Research Fellowship 1,059,660.
Compliance with ethical standards
Conflict of interest
The authors declare that over the past three years, Brian Harvey has participated in advisory boards and received honoraria from Servier®, and has received research funding from Servier® and Lundbeck®. The authors declare that, except for income from the primary employer and research funding to BHH from the above-mentioned organizations and agencies, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional services, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
- Ashton M, Berk M, Ng C, Hopwood M, Harvey B, Dean O (2016) The efficacy of adjunctive Garcinia Mangostana Linn pericarp for bipolar depression: a 24-week double-blind, randomised, placebo controlled trial. Bipolar Disord 18:168–168Google Scholar
- Baldessarini RJ (2006) Drug therapy of depression and anxiety disorders. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Edited by Brunton LL, Lazo JS, Parker KL. 429–460Google Scholar
- Berk M, Dean OM, Cotton SM, Jeavons S, Tanious M, Kohlmann K, Hewitt K, Moss K, Allwang C, Schapkaitz I, Robbins J, Cobb H, Ng F, Dodd S, Bush AI, Malhi GS (2014) The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J clin psychiatry 75:628–636CrossRefPubMedGoogle Scholar
- Brocardo PS, Boehme F, Patten A, Cox A, Gil-Mohapel J, Christie BR (2012) Anxiety-and depression-like behaviors are accompanied by an increase in oxidative stress in a rat model of fetal alcohol spectrum disorders: protective effects of voluntary physical exercise. Neuropharmacology 62:1607–1618CrossRefPubMedGoogle Scholar
- Chenu F, El Mansari M, Blier P (2013). Electrophysiological effects of repeated administration of agomelatine on the dopamine, norepinephrine, and serotonin systems in the rat brain. Neuropsychopharmacology 38:275–284Google Scholar
- Chiu K, Lau WM, Lau HT, So KF, Chang RCC (2007) Micro-dissection of rat brain for RNA or protein extraction from specific brain region. JoVE 7:e269–e269Google Scholar
- Du Jardin KG, Liebenberg N, Müller HK, Elfving B, Sanchez C, Wegener G (2016) Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression Psychopharmacology (Berl) 233(14):2813–2825.Google Scholar
- Garrity AR, Morton GA, Morten JC (2004) Nutraceutical mangosteen composition. 6730333 B1 20040504. US Patent. 7Google Scholar
- Gemmel M, Rayen I, Lotus T, van Donkelaar E, Steinbusch HW, De Lacalle S, Kokras N, Dalla C, Pawluski JL (2016). Developmental fluoxetine and prenatal stress effects on serotonin, dopamine, and synaptophysin density in the PFC and hippocampus of offspring at weaning. Dev Psychobiol 58:315–327Google Scholar
- Harvey BH, Duvenhage I, Viljoen F, Scheepers N, Malan SF, Wegener G, Brink CB, Petzer JP (2010) Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues. Biochem Pharmacol 80:1580–1591CrossRefPubMedGoogle Scholar
- Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412Google Scholar
- Köhler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O, Krogh J (2014) Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 71:1381–1391CrossRefPubMedGoogle Scholar
- Leonard B, Maes M (2012) Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev 36:764–785CrossRefPubMedGoogle Scholar
- Márquez L, García-Bueno B, Madrigal JL, Leza JC (2012) Mangiferin decreases inflammation and oxidative damage in rat brain after stress. Eur. J Nutr 51:729–739Google Scholar
- Márquez-Valadez B, Lugo-Huitrón R, Valdivia-Cerda V, Miranda-Ramírez LR, Pérez-De La Cruz V, González-Cuahutencos O, Rivero-Cruz I, Mata R, Santamaría A, Pedraza-Chaverrí J (2009) The natural xanthone alpha-mangostin reduces oxidative damage in rat brain tissue. Nutr Neurosci 12:35–42CrossRefPubMedGoogle Scholar
- Möller M, Harvey BH, Du Preez JL, Emsley R (2011) Isolation rearing-induced deficits in sensorimotor gating and social interaction in rats are related to cortico-striatal oxidative stress, and reversed by sub-chronic clozapine administration. Eur Neuropsychopharmacol 21:471–483CrossRefPubMedGoogle Scholar
- Morley-Fletcher S, Darnaudery M, Mocaer E, Froger N, Lanfumey L, Laviola G, Casolini P, Zuena A, Marzano L, Hamon M (2004) Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT 1A receptor mRNA in prenatally stressed rats. Neuropharmacology 47:841–847CrossRefPubMedGoogle Scholar
- Negi J, Bisht V, Singh P, Rawat M, Joshi G (2013) Naturally occurring Xanthones: chemistry and biology. J Appl Chem 2013:1Google Scholar
- Talbott SM, Morton DA, Templeman JF (2011) Mangosteen–traditional and modern uses. J Austr Integrative Med Ass 16(1):10–11Google Scholar
- Uys M, Shahid M, Sallinen J, Harvey BH (2017) The α2C-adrenoceptor antagonist, ORM-10921, exerts antidepressant-like effects in the flinders sensitive line rat. Behav. Pharmacology 28:9–18Google Scholar