http://adhlui.com.ui.edu.ng/jspui/handle/123456789/21 Theses in Pharmacology and Therapeutics Thu, 26 Feb 2026 03:37:32 GMT 2026-02-26T03:37:32Z http://adhlui.com.ui.edu.ng/jspui/handle/123456789/809 Title: ANTI-STRESS POTENTIALS AND THE MECHANISM OF ACTION OF MORIN HYDRATE IN SWISS MICE Authors: OLONODE, E. T. Abstract: Stress, is an integral component of life that distorts body homeostasis. The available anti-stress drugs are often ineffective in combating its multiple effects. Adaptogens with antioxidant and neuroprotective effects are known to relieve stress. Morin hydrate (MH), a flavonoid from Morus alba with known antioxidant and neuroprotective properties has not been investigated for its anti-stress potential. The study was designed to investigate the anti-stress property of MH and its mechanisms of action in mice. Eighty male Swiss mice (22.0 ± 2.5 g) were used for acute studies: Swimming Endurance Test (SET), Anoxic Tolerance Test (ATT) and Acute Restraint Stress (ARS). The SET and ATT consisted of 5 treatment groups each (n = 5): vehicle (normal saline, 10 mg/mL), MH (5, 10, 20 mg/kg) and adaptogen (ginseng, 25 mg/kg), administered intrapertioneally. Thirty minutes later immobility time was measured in SET and convulsion latency in ATT. In ARS, thirty male mice were allotted into treatment groups I-VI (n = 5): vehicle(10 mg/mL), vehicle-stress control (10 mg/mL), MH (5, 10, 20 mg/kg) and ginseng (25 mg/kg), and treated for 7 days prior to being restrained except group 1. Thereafter, mice were assessed for anxiety and depression in Elevated-Plus Maze (EPM) and Forced-Swim Test (FST), respectively. For chronic studies, ninety male mice were used in 3 models [Chronic- Restraint Stress (CRS), Paradoxical Sleep-deprivation (PSD) and Chronic-Unpredictable Stress (CUS) and grouped, respectively as in ARS. In CRS, mice were pre-treated and restrained for 14 days, and thereafter assessed for anxiety and depression in Mice were sleep-deprived for 48 hours in PSD, and exposed to stressors for 14 days in CUS before testing for memory and anxiety behaviours using Y-maze and EPM, respectively. Brain glutathione (GSH), malondialdehyde, nitric-oxide and blood glucose were determined spectrophotometrically in ARS, CRS, PSD and CUS. Serum corticosterone, brain tumor necrosis factor-alpha (TNF-α) and interleukin-l beta were measured in CUS using ELISA. Brain nuclear factor-kB (NF-kB) and inducible nitric-oxide synthase (iNOS) expressions in CUS were measured using immunohistochemistry. Data were analysed using ANOVA at α0.05. Morin hydrate (5, 10, 20 mg/kg) significantly reduced immobility (10.8 ± 0.20, 7.04 ± 0.77, 9.16± 0.59 s against 11.9 ± 0.25 s) in SET and prolonged convulsion latency ATT (33.1 ± 1.26, 34.1 ±2.40, 34.8 ± 1.06 s against 21.9 ± 1.15 s).The MH decreased anxiety, depression-like symptoms, malondialdehyde and nitric-oxide but increased GSH in ARS and CRS. The MH reversed memory impairment (65.87 ± 3.59, 69.17 ± 6.51, I 62.0± 5.12% against 50.87 ± 2.87%) and anxiety (64.75 ± 5.36, 57.75 ± 2.95, 61.00 ± 1.68 s against 45.0 ± 1.87 s) in PSD. Also, MH increased GSH (104.6 ± 8.50, 97.3 ±6.51, 91.5 ± 7.70 µmol/g tissue against 50.22 ±1.41 µmol/g tissue) but decreased malondialdehyde (7.57± 0.25, 4.50 ± 0.13, 3.16 ± 0.22 µmol/g tissue against 8.60 ± 0.14 µmol/g tissue) and nitric-oxide (163.0 ± 8.67, 121.3 ± 6.67, 124.7± 3.33 µmol/g tissue against 338.0 ± 16.77 µmol/g tissue). The MH increased GSH concentration in CUS and ameliorated CUS-induced increases in glucose, malondialdehyde and nitric oxide Ievels compared to controls. Morin hydrate reduced corticosterone (7.93 ± 0.19, 7.18 ±0.21, 7.46 ± 0.20 ng/mL. against 8.54 ±0.14 ng/mL), TNF-α (49.19 ± 0.55, 47.60± 2.48, 35.22 ± I .77 pg/mL against 92.37± 7.90 pg/mL), and interleukin-I beta (74.45 ± 2.18. 46.45 ± 2.71 43.12 ± 1.55 pg/mL, against 98.72 ± 4.03 pg/mL). Morin hydrate reduced iNOS and NF-kB protein levels in CUS. Morin hydrate exhibited anti-stress potential via mechanisms related to inhibition of hypothalamic-pitutary-adrenal axis hyperactivation, oxidative stress and neuroinflammation. Description: A Thesis in the Department of Pharmacology and Therapeutics, submitted to the Faculty of Basic Medical Sciences in partial fulfillment of the requirement for the Degree of Doctor of Philosophy of the University of Ibadan, Ibadan Wed, 01 Aug 2018 00:00:00 GMT http://adhlui.com.ui.edu.ng/jspui/handle/123456789/809 2018-08-01T00:00:00Z http://adhlui.com.ui.edu.ng/jspui/handle/123456789/808 Title: EVALUATION OF MECHANISMS UNDERLYING ANTIDEPRESSANT-LIKE EFFECT OF METHYL JASMONATE IN MICE Authors: UGBOMAH, A.N Abstract: Depression is a chronic, recurrent and severe disease that affects millions of individuals worldwide and impairs the quality of life of the patients. The clinical efficacy of existing antidepressants has been compromised by adverse effects, low remission and delayed onset of action thus necessitating search for alternative agents. Methyl jasmonate (MJ), isolated from Jasminum grandiflorum has antidepressant activity but the mechanisms of action remains unknown. This study was designed to elucidate the class of antidepressants and mechanisms by which MJ elicit antidepressant effect in mice. One hundred and fifteen male Swiss mice (22±1.5g) were used and treated intraperitoneally. Twenty five mice were assigned to 5 groups (n=5): vehicle (distilled water; 10 mL/kg), MJ (5, 10, 20 mg/kg) and imipramine (10 mg/kg), respectively 30 minutes prior to forced swim test (FST) and tail suspension test (TST). Immobility time served as depressive-like behaviour in both tests. For interaction with monoaminergic blockers, 30 mice were allotted to 6 groups (n=5): prazosin (62.5 µg/kg), yohimbine (1 mg/kg), haloperidol (0.2 mg/kg), sulpiride (50 mg/kg), p-Chloro-phenylalanine (100 mg/kg) and metergoline (4 mg/kg), 15 minutes prior to MJ (20 mg/kg), respectively and were subjected to TST, 30 min after MJ treatment. In lipopolysaccharide (LPS) model, 30 mice were allotted into 6 groups (n=5). Groups 1 and 2 received vehicle (10 mL/kg), while groups 3-6 received MJ (5, 10, 20 mg/kg) and imipramine (10 mg/kg), respectively. A week after, groups 2-6 received a single dose of LPS (0.83 mg/kg; i.p) and depressive-like behaviour was assessed using sucrose preference test. In Chronic Unpredictable Mild Stress (CUMS) model, 30 mice (n=5) were similarly grouped as in LPS model. Groups 2-6 were exposed to stressors for 2 weeks and 24 hours later, TST was used to assess depressive-like symptom. Brain homogenates of LPS-treated and CUMS mice were used to determine malondialdehyde, superoxide dismutase (SOD) and reduced glutathione (GSH) by spectrophotometry, while Tumour Necrosis Factor-alpha (TNF-α) and corticosterone were determined by ELISA. Data were analysed using descriptive statistics and ANOVA at α0.05. Methyl jasmonate (5, 10, 20 mg/kg) significantly reduced immobility time in TST (77.50±5.41, 111.8±1.27, 71.52±8.87 s) and FST (99.93±3.24, 90.75±6.40, 71.28±6.70 s) compared to controls (139.40±7.40; 113.4±3.55 s). Monoaminergic antagonists increased immobility time with MJ in TST. In LPS model, MJ increased sucrose preference (53.75±7.47, 60.52±9.42, 61.60±6.74%) versus control (22.50±3.23%). The MJ decreased corticosterone (1.36±0.17, 0.77±0.24, 0.56±0.08 ng/mL), TNFα (16.96±0.52, 17.70±1.59, 12.52±0.26 pg/mL) and malondialdehyde (30.89±2.47, 68.15±3.95, 40.02±1.38 µmol/g tissue) relative to controls (2.68±0.20 ng/mL; 20.67±1.81 pg/mL; 99.88±1.80 µmol/g tissue). The MJ increased GSH concentration and SOD activity. In CUMS model, MJ decreased immobility time (89.60±3.17, 81.00±4.34, 76.20±2.71 s) in TST compared to control (161.00±5.43 s). It also decreased corticosterone, TNFα and malondialdehyde levels compared to controls in LPS model. The MJ also increased GSH concentration (13.27±0.47, 16.41±0.62, 18.93±0.38 μmol/g tissue) and SOD activity (1.77±0.22, 4.38±0.35, 4.79±0.13 units/mg protein) compared to stressed-controls (6.47±0.64 μmol/g tissue; 0.90±0.03 units/mg protein). Methyl jasmonate exhibited antidepressant-like effect via enhancement of monoaminergic neurotransmission, reduction of brain corticosterone, attenuation of oxidative stress and neuroinflammation. Description: A thesis in the department of Pharmacology and therapeutics, submitted to the faculty of Basic Medical Sciences in partial fulfilment of the requirements for the degree of Doctor of Philosophy of the University of Ibadan Wed, 01 Nov 2017 00:00:00 GMT http://adhlui.com.ui.edu.ng/jspui/handle/123456789/808 2017-11-01T00:00:00Z http://adhlui.com.ui.edu.ng/jspui/handle/123456789/803 Title: EVALUATION OF THE ANTI-INFLAMMATORY ACTIVITIES OF EXTRACTS AND FLAVONOID-RICH FRACTION FROM Ocimum gratissimum LINN.(LAMIACEAE) LEAF Authors: AJAYI, A. M. Abstract: Inflammatory responses are among causes of ill health, impaired quality of life and untimely death. Naturally occurring phenolics are sale phytochemicals that provides combinatorial multitargeted therapy in chronic inflammatory diseases. Ocimum gratissimum (Og) leaves due to its richness in phenolic compounds, have been used in managing inflammation-related diseases. This study was designed to evaluate the anti-inflammatory activity of extracts from Og and the mechanisms of its flavonoid-rich fraction. Ocimum gratissimum leaves obtained from a domestic garden at lkoloba Ibadan was authenticated at Forest Herbarium Ibadan (FHI 110191). Powdered Og leaf was sequentially extracted in n-hexane (HE0g), chloroform (CE0g) and methanol (ME0g) by maceration. Anti-inflammatory activity of the extracts were screened in 25 female Wistar rats, divided into five groups (n=5) of control (1% tween 80), Indometttacin (10 mg/kg), HEOg, CEOg and MEOg at 400 mg/kg using carrageenan-induced paw oedema. The flavonoid-rich fraction (EAFOg) was obtained from MEOg by partitioning with ethylacctate, and flavonoids identified by High Performance Liquid Chromatography using authentic standards. Air pouch was induced for 6 days in 60 female Wistar rats randomly allotted into 12 treatment groups. Groups 1-6 were divided into saline, carrageenan, EAFOg (50, 100 mg/kg), SC58125 (1 mg/kg: COX-2 inhibitor) and indomethacin (5 mg/kg) while groups 7-12 were divided into saline, lipopolysaccharide, EAFOg (25, 50, 100 mg/kg), indomethacin (5 mg/kg). Groups 2-6 were challenged with carrageenan for 24 h and 8-12 with LPS for 6 h. Pouch exudates were measured and leucocytes counts determined by microscopy. Nitric Oxide (NO), malondialdehyde (MDA), reduced glutathione (GSH) levels and activities of myeloperoxidase (MPO) and superoxide dismutase (SOD) were determined spectrophotometrically. Tumour Necrosis Factor-alpha (TNF-α) and Prostaglandin E₂ (PGE₂) were determined by ELISA. In vitro inhibitory effect on NO, Interleukin (IL)-1 1β-10, TNF-α release were assayed in LPS stimulated RAW 264.7 cells. Inhibitory activity on cyclooxygenase-1/2 and 15-lipoxygenase enzymes were determined spectrophotometrically. Data were analysed using descriptive statistics and ANOVA at α0.05. The MEOg reduced oedema volume (0.54 ±0.09 mL) relative to control (1.37 ±0:15 mL). The HPLC revealed presence of rutin (1.131 ug/mg), ellagic acid (11.655 ug/mg), myricetin (6.535 ug/mg) and morin (0.073 ug/mg) in EAFOg. The EAFOg (50, 100 mg/kg) reduced exudates volume (1.67± 0.07, 0.77 ± 0.12 mL) and neutrophil counts (23.26 ± 3.32, 18.58 ± 0.74) compared to carrageenan-only (2.60 ± 0.06mL 62.09 ± 7.47), respectively. The EAFOg (25, 50, 100 mg/kg) significantly reduced neutrophil count (3.53 ± 0.28, 1.99 ± 0.34, 2.06 ± 0.29) and PGE₂ (223.20 ± 5.01, 187.90± 8.69, 165.20 ± 14.93 pg/mL) in LPS air pouch relative to LPS-only (4.45 ± 0.28; 242.20 ± 8.33 pg/mL), respectively. The ENFOg reduced TNT- α, NO, MPO, MDA but increased GSH and SOD compared to control. In vitro, EAFOg reduced NO, IL-Iβ, IL-10 and TNF- α release in LPS-stimulated RAW 264.7 cells and preferentially inhibited COX-2 (IC₅₀ =48.86) relative to COX- 1 and I5-LO (IC₅₀ >100). The flavonoid-rich fraction of Ocimum gratissimum leaves demonstrated potent anti inflammatory activities through mechanisms related to inhibition of neutrophil migration, pro-inflammatory cytokines, cyclooxygenase-2 and oxidative stress. Description: A Thesis in the Department of Pharmacology and Therapeutics, submitted to the Faculty of Basic Medical Sciences in partial fulfillment of the requirements for the Degree of Doctor of Philosophy of the University of Ibadan Tue, 01 Aug 2017 00:00:00 GMT http://adhlui.com.ui.edu.ng/jspui/handle/123456789/803 2017-08-01T00:00:00Z http://adhlui.com.ui.edu.ng/jspui/handle/123456789/796 Title: EVALUATION OF THE ANTISPYCHOTIC PROPERTY OF MORIN AND ITS MECHANISMS OF ACTION IN EXPERIMENTAL MICE Authors: BEN-AZU, B Abstract: Psychosis is a chronic neuropsychiatric disease characterised by severe behavioural perturbations. Current drugs used in the management of the disease are associated with serious side effects. Therefore, compounds with psychotropic-antioxidant effects are currently being sought as alternatives. Morin, a naturally-occurring neuroactive flavonoid isolated from Morusalba possesses strong psychotropic and antioxidant properties, however the mechanism of the antipsychotic property has not been fully elucidated. This study was designed to investigate the antipsychotic-like activity of morin and its mechanisms of action in mice. Morin was administered intraperitoneally to male Swiss mice. Ninety mice randomised into 6 groups of each experiment (n=5): vehicle (normal saline, 10mL/kg), morin (25, 50, 100mg/kg), haloperidol (1mg/kg) and risperidone (0.5mg/kg); were pre-treated to assess the acute antipsychotic effects of morin on apomorphine-(2mg/kg), ketamine-(10mg/kg) induced stereotypes and woodblock-catalepsy test. For the chronic studies, fifty mice were given preventive treatments (n=5) with morin (100mg/kg/day), haloperidol (1mg/kg/day), risperidone (0.5mg/kg/day), or vehicle for 14 days prior to injection of ketamine (20mg/kg/day) from the 8th-14th day. For the reversal treatment, animals received ketamine for 14 days prior to the treatments. The antipsychotic and neuroinflammatory effects were also assessed in 25 mice following pretreatments with vehicle, morin, haloperidol and risperidone, in combination with lipopolysaccharide (0.1mg/kg/day) induced neuroinflammation for 14 days prior to ketamine (20mg/kg/day) treatment from the 8th-14th day. Schizophrenia-like behaviours in all chronic studies were evaluated using open-field, social-interaction and Y-maze tests. Thereafter, brain biomarkers of oxidative/nitrergic stress were determined, spectrophotometrically in specific-brain regions (striatum, prefrontal cortex and hippocampus) in preventive-reversal and neuroinflammatory studies. Specific-brain regions of dopamine, glutamate and serotonin concentrations, Glutamic Acid Decarboxylase-67 (GAD67), Brain-Derived Neurotrophic Factor (BDNF) and gp91-phox expressions were measured in the preventive-reversal study using ELISA or immunohistochemistry. Brain Tumor Necrosis Factor-alpha (TNF-α),interleukin-6 levels, cyclooxygenase-2 (COX-2) and Nuclear Factor-κB (NFκB) expressions were determined in the neuroinflammatory study using ELISA or immunohistochemistry. Dendritic arborization of the cortical pyramidal neurons of lipopolysaccharide-ketamine treated mice was assessed using silver-impregnation stain. Data were analysed using descriptive statistics and ANOVA at α0.05. Morin (25, 50, 100mg/kg) significantly suppressed stereotypy induced by apomorphine (23.4, 34.5 and 60.1%) and ketamine (33.7, 73.4 and 83.4%) relative to controls,and was devoid of extrapyramidal side effects in catalepsy test.Morin (100mg/kg) prevented and reversed ketamine-induced social and cognitive deficits relative to controls and ketamine-induced hyperlocomotion (61.6±5.2 vs109.8±5.3; 47.0±6.1 vs103.2±4.5), respectively. Morin prevented and reversed altered dopaminergic, glutamatergic, GABAergic and serotonergic neurotransmissions in the striatum, prefrontal cortex and hippocampus, respectively. Morin increased BDNF, glutathione, and decreased malondialdehyde, nitrite levels and pg91-phox expressions in the three brain regions. Morin reduced TNF-α (124.7±8.6 vs212.7±9.4; 117.3±9.7 vs278.5±13.9 pg/g tissue) in the striatum and prefrontal cortex, and morin also reduced interleukin-6 (321.3±24.2 vs704.7±26.3, 295.1±19.7 vs581.3±47.4 pg/g tissue) in the prefrontal cortex and hippocampus. It also reduced COX-2 and NFκB expressions in the three brain-regions, and increased dendritic arborization of the cortical-pyramidal neurons. Morin demonstrated antipsychotic-like activity via mechanisms related to modulation of neurotransmitters, enhancement of neurotrophin, inhibition of oxidative/nitrergic stress and neuroinflammation. Description: A thesis in the department of pharmacology and therapeutics, submitted to the faculty of Basic Medical Sciences in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of the University of Ibadan Fri, 01 Jun 2018 00:00:00 GMT http://adhlui.com.ui.edu.ng/jspui/handle/123456789/796 2018-06-01T00:00:00Z