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Antidepressant Activity of Spathodea Campanulata in Mice and Predictive Affinity of Spatheosides Towards Type a Monoamine Oxidase

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Antidepressant Activity of Spathodea Campanulata in Mice and Predictive Affinity of Spatheosides Towards Type a Monoamine Oxidase 1 Antidepressant activity of Spathodea 2 campanulata in mice and predictive affinity 3 of spatheosides towards type A monoamine 4 oxidase 5 6 7 8 Jitendra Bajaj1, Jaya Dwivedi2*, Ram Sahu3, Vivek Dave1, Kanika Verma1, Sushil 9 Joshi4, Bhawana Sati1, Swapnil Sharma1, Veronique Seidel5*, Abhay Prakash 10 Mishra6* 11 12 1Department of Pharmacy, Banasthali Vidyapith, Banasthali, P.O. Rajasthan-304022-India 13 2Department of Chemistry, Banasthali Vidyapith, Banasthali, P.O. Rajasthan-304022-India 14 3Department of Pharmaceutical Sciences, Assam University (A Central University), Silchar 788011- India 15 4R&D, Patanjali Ayurved Ltd, Patanjali Food and Herbal Park, Haridwar, Uttarakhand, India 16 5Natural Products Research Laboratory, Strathclyde Institute of Pharmacy and Biomedical Sciences, 17 University of Strathclyde, Glasgow, UK. 18 6Department of Pharmaceutical Chemistry, Hemwati Nandan Bahuguna Garhwal University, Srinagar 19 Garhwal-246174, Uttarakhand, India. 20 21 Corresponding authors: 22 [email protected] 23 [email protected] 24 [email protected] 25 26 27 28 29 30 This is a peer reviewed, accepted author manuscript of the following research article: Bajaj, J. et al. (2021). Antidepressant activity of Spathodea campanulata in mice and predictive affinity of spatheosides towards type A monoamine oxidase. Cellular and Molecular Biology, 67(1). https://doi.org/10.14715/cmb/2021.67.1.1 31 ABSTRACT 32 The antidepressant activity of Spathodea campanulata flowers was evaluated in mice and in silico. When 33 tested at doses of 200 and 400 mg/kg, the methanol extract of S. campanulata (MESC) showed dose- 34 dependent antidepressant activity in the force swim test (FST), tail suspension test (TST), lithium chloride- 35 induced twitches test and the open field test. In FST and TST, animals treated with MESC demonstrated a 36 significant decrease in the immobility period compared to the control group. The lithium chloride-induced 37 head twitches were significantly reduced following administration of MESC. The latter, at the dose of 400 38 mg/kg, also significantly reduced locomotor activity. Following administration of MESC, changes in the 39 levels of serum corticosterone, and of norepinephrine, dopamine, serotonin, 4-hydroxy-3- 40 methoxyphenylglycol (MHPG), 4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindoleacetic acid 41 (5-HIAA) were measured in different brain regions using HPLC. The presence of spatheoside A (m/z 541) 42 and spatheoside B (m/z 559) in MESC was detected using HPLC/ESI-MS. These two iridoids demonstrated 43 a high predictive binding affinity for the active site of the type A monoamine oxidase (MAO-A) enzyme 44 with scores of 99.40 and 93.54, respectively. These data suggest that S. campanulata flowers warrants 45 further investigation as a source of novel templates for antidepressive drugs. 46 47 48 Keywords: Antidepressant activity, Depression; Monoamines, Molecular docking, Spathodea 49 campanulata 50 51 52 1. INTRODUCTION 53 Depression is a common and serious psychiatric disorder that is a major contributor to the global burden of 54 disease. According to the World Health Organisation, an estimated 322 million people worldwide suffer 55 from depression (1). It has been reported that reactive oxygen species (ROS) and nitrogen species play an 56 important part in the pathogenesis of depression by regulating the levels and activity of noradrenaline 57 (norepinephrine), serotonin, dopamine and glutamate, the principal neurotransmitters involved in the 58 neurobiology of depression (2). Several classes of antidepressant drugs (i.e. tricyclic antidepressants, 59 selective serotonin reuptake inhibitors, selective reversible inhibitors of monoamine oxidase A, and specific 60 serotonin–norepinephrine reuptake inhibitors) are used currently to treat depression However, a high 61 number of side effects (e.g. sexual dysfunction) have been reported with these drugs and there is a need to 62 discover an effective alternative treatment for depression that is better tolerated (3). 63 A variety of medicinal plants are used as antidepressants in traditional medicine (4) and/or contain some 64 chemical constituents that have already demonstrated antidepressant activity (5). Spathodea campanulata 65 Beauv. (Bignoniaceae), known as the African tulip tree, is native to Africa but commonly distributed 66 throughout South America, the Caribbean and the Pacific Isles (6). Traditionally, S. campanulata is useful 67 for the treatment of fever, dysentery, constipation, malaria, diabetes and skin diseases (7). The species is 68 reported to contain some iridoids, flavonoids, tannins, saponins, alkaloids, terpenoids and steroids (8-10). 69 Previous reports have suggested that phytochemicals like iridoids, flavonoids, alkaloids and tannins have 70 antidepressant activity (11,12). To the best of our knowledge, the antidepressant activity of S. campanulata 71 and its constituents as yet to be evaluated. The present study was performed to evaluate the antidepressant 72 activity of S. campanulata flowers in different mice models. Further alteration in the levels of monoamines 73 such as norepinephrine (NE), dopamine (DA), serotonin (5-HT), and their respective metabolites 4- 74 hydroxy-3-methoxyphenylglycol (MHPG), 4-dihydroxy-phenylacetic acid (DOPAC), and 5- 75 hydroxyindoleacetic acid (5-HIAA) in different regions of mice brains following administration of S. 76 campanulata extracts. The role of corticosterone in anxiety/depression was also investigated by measuring 77 its serum levels in treated versus untreated animals. A molecular docking study was performed to 78 investigate the predictive binding affinity of two iridoids identified within S. campanulata, spatheoside A 79 and spatheoside B, towards the type A monoamine oxidase enzyme. 80 81 2. MATERIALS AND METHODS 2 82 2.1 Plant collection and identification 83 Spathodea campanulata flowers were collected in Mannargudi and around Thiruvarur (Dt), Tamil Nadu, 84 India in the month of July and August 2012. The plant was identified and authenticated by Dr. Soosairaj, 85 Department of Botany, St. Joseph’s College, Trichirappalli, Tamil Nadu, India, where a voucher specimen 86 number (SJCBOT 1563/2013) has been deposited. 87 88 2.2 Extraction of plant material 89 The flowers were air dried in the shade for 10-15 days and the dried material (246 g) was ground to a fine 90 powder and stored in air tight bottles. Extraction was performed by maceration at room temperature with 91 ethyl acetate and then methanol (10% w/v) for 72 h with intermittent shaking to afford EAESC and MESC, 92 respectively. Following filtration, the extracts were concentrated under reduced pressure at < 40 °C and 93 were stored in desiccators. The yields obtained were 5.03 and 6.37 % DW for EAESC and MESC, 94 respectively. 95 96 2.3 Preliminary phytochemical investigation 97 Extracts were screened for presence of flavonoids, tannins, saponins, alkaloids, terpenoids and steroids 98 using standard methods (8, 13,14). 99 100 2.4 Experimental animals 101 Male Swiss albino mice (25-40 g) were used for all experiments. The animals (four per cage) were sheltered 102 under conventional laboratory conditions of temperature (25 ± 2 °C) with a 45-55% relative humidity and 103 a 12/12 h light/dark cycle (15). Sterile husk paddy was used as bedding material. Standard pellets (Golden 104 feeds, New Delhi) were used as the standard diet with the availability of water ad libitum. Pellets were 105 withdrawn (but not water) 4 h prior to the administration of extracts and/or drug until completion of all 106 experiments on the day. Animals were transferred 1 h prior to an experiment to an experimental room for 107 adaptation purposes. Ethical approval was obtained from the Institutional Animal Ethical Committee (Ref 108 no PBRI/IAEC/PN-15014). All experimental studies were carried out according to the guidelines from the 109 Committee for the Purpose of Control and Supervision of Experiment on Animals. 110 111 2.5 Acute toxicity 112 This study was performed according to Annex 2a of the OECD guidelines (16). The animals were divided 113 into groups (n = 6) which received increasing oral doses (5, 50, 300 and 2000 mg/kg) of MESC. The control 114 group received sterile distilled water (SDW). After 24 h, the general signs and symptoms of toxicity and 115 mortality rates in each group were recorded. 116 117 2.6 Antidepressant activity 118 Antidepressant activity was studied by observing the behaviour of individual mice in response to a stressful 119 stimulus which it cannot escape from in the force swim test and the tail suspension test. The animals (n = 120 6) were divided in groups I–VI, where group I received SDW (negative control), group II-VI were treated 121 orally with 20 mg/kg amitriptyline, 200 and 400 mg/kg EAESC, and 200 and 400 mg/kg MESC, 122 respectively. 123 124 2.6.1 Forced Swim Test (FST) 125 In this test, after treatment, each animal from group I-VI was positioned gently into water (up to 20 cm) in 126 transparent cylindrical polyethylene tanks (25 cm high, 10 cm internal diameter) for 6 min. When an animal 127 stopped swimming - swimming being a normal escape response mechanism - and floated on the surface of 128 the water, it was considered it had “given up” (a characteristic reported to be similar to depression in 129 humans). The duration of immobility (in seconds) was assessed during the last 4 minutes of the test (17). 130 131 2.6.2 Tail Suspension Test (TST) 3 132 In this test, after treatment, the mice were hanged, with the help of adhesive tape placed approximately 1 133 cm from the tip of their tails, 58 cm above the floor for a period of 6 minutes. The duration of immobility 134 (in seconds) produced by the tail suspension was recorded during the last 4 minutes of the test (18). 135 136 2.6.3 Lithium chloride-induced head twitches 137 The mice were randomly divided in five groups (n = 6), where group I received the vehicle (SDW), group 138 II received lithium chloride (100 mg/kg, intraperitoneally), group III-V were treated with amitriptyline (20 139 mg/kg, p.o), 200 and 400 mg/kg MESC, respectively.
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