DSpace Community: FACULTY OF BASIC MEDICAL SCIENCES

PROTECTIVE EFFECT OF Pterocarpus mildbraedii HARMS EXTRACT ON PROPANIL-INDUCED HEPATOTOXICITY AND ALTERATIONS IN APOPTOTIC-RELATED PROTEINS IN WISTAR RATS

Mon, 01 May 2017 00:00:00 GMT

Title: PROTECTIVE EFFECT OF Pterocarpus mildbraedii HARMS EXTRACT ON PROPANIL-INDUCED HEPATOTOXICITY AND ALTERATIONS IN APOPTOTIC-RELATED PROTEINS IN WISTAR RATS Authors: OTUECHERE, C.A Abstract: One of the probable causes of liver diseases is exposure to environmental chemicals. Agrochemicals containing propanil are known to induce hepatic toxicity. Pterocarpus mildbraedii leaf is used in traditional medicine to treat various disorders without scientific justification. This study was designed to investigate the protective role of extract of Pterocarpus mildbraedii against propanil-induced hepatotoxicity in rats. Pterocarpus mildbraedii leaves, purchased from Oyingbo market, Lagos State, were authenticated at the University of Lagos Herbarium (LUT/5913). Powdered leaf was extracted in soxhlet, using dichloromethane:methanol (1:1), to yield crude extract of Pterocarpus mildbraedii (PME). Sixty-four male Wistar rats (130-160 g), comprising of eight groups (n=8) were used for these experiments. Rats were treated orally with normal saline (control), PME (100 mg/kg), PME (200 mg/kg), PME (400 mg/kg), propanil (200 mg/kg), PME (100 mg/kg) + propanil (200 mg/kg), PME (200 mg/kg) + propanil (200 mg/kg) and PME (400 mg/kg) + propanil (200 mg/kg) for seven consecutive days. Hepatic tissues and serum were assayed for markers of hepatic damage, oxidative stress, inflammation, and apoptosis. Aspartate aminotransferase (AST), lactate dehydrogenase (LDH), bilirubin (BIL), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), malondialdehyde (MDA), myeloperoxidase (MPO) and nitric oxide (NO) were assayed by spectrophotometry. Inducible Nitric Oxide Synthase (iNOS), Cyclooxygenase-2 (COX-2), Nuclear factor kappa B (NF-κB), Caspase 3, Caspase 9, Bax, Bcl-2 expressions were measured using immunohistochemistry. Tumour suppressor p53, Bcl-2 antagonist of cell death (Bad), NF-κB, inhibitor of total nuclear factor-kappa B α (IκB α), stress activated protein kinase/ C Jun NH2-terminal kinase (SAPK/JNK), p38 mitogen-activated protein kinase (p38) and signal transducer and activator of transcription 3 (STAT 3) were assessed by ELISA. Histopathology of liver was determined by microscopy and apoptosis by TUNEL assay. Data were analysed using ANOVA at α0.05. The yield of PME was 41.9%. Administration of propanil significantly increased AST (132.10±6.32 U/L), LDH (85.70±6.60 U/L), BIL (1.15±0.16 mg/dL), SOD (0.97±0.05 U/mg protein), MDA (1.03±0.08 µgMDA/mg protein), MPO (4.98±0.12 µmol/min/mg protein) and NO (0.38 µmol/mg protein) relative to control (115.90±8.65, 32.84±9.39, 1.15±0.16, 0.38± 0.01, 0.40±0.11, 2.47±0.10 and 0.19± 0.05, respectively). Pre-treatment of propanil-exposed rats with PME (200 mg/kg) significantly decreased LDH (83%), BIL (50%), SOD (50.5%), MDA (33.1%), MPO (63.3%) and NO (59.5%). Further, propanil administration decreased the levels of GSH (2.98±0.24 µg/mg protein) and CAT (52.7±0.24 µmol H202 consumed/min/g tissue) when compared with the controls (2.04±0.09 and 51.00±0.51). However, intervention with PME restored these serum biochemical indices and antioxidant parameters back to normal values. Expressions of iNOS, COX-2, NFκB, Caspase 3, Caspase 9 and Bax were higher in the propanil group relative to control. Levels of signaling mediators p38 (81.28±7.70), STAT 3 (88.80±4.40) and NF-κB (72.76± 5.30) were lower, while SAPK (125.39±9.30), IκB α (115.83±5.60) and Bad (112.48±4.70) were higher in propanil-treated rats relative to control value set at 100. TUNEL-positive nuclei and severe periportal fibrosis were observed in tissues following propanil exposure. However, pre-treatment with PME significantly attenuated the observed propanil-induced inflammation and apoptosis. Pterocarpus mildbraedii extract protected against propanil-induced hepatotoxicity via mechanisms that involved its antioxidant, anti-inflammatory and anti-apoptotic properties. Description: A Thesis in The Department Of Biochemistry 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

DETERMINANTS OF RESPONSES TO ANTIMALARIAL DRUGS IN CHILDREN WITH UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA

Sun, 01 May 2011 00:00:00 GMT

Title: DETERMINANTS OF RESPONSES TO ANTIMALARIAL DRUGS IN CHILDREN WITH UNCOMPLICATED PLASMODIUM FALCIPARUM MALARIA Authors: SIJUADE, A.O Abstract: Drug resistance is a challenge to malaria control efforts and several factors including parasite genetics, host factors and pharmacokinetics may contribute to the selection of drug resistant Plasmodium falciparum. Understanding the role of these factors in patient response to antimalarial drugs is therefore essential in the management of malaria. The aim of the study was to determine the factors contributing to delay in malaria Parasite Clearance (PC) in children and evaluating the effects of pharmacokinetic variability on treatment outcome. Children (n=2,752), aged 6 months -12 years, with falciparum malaria, were enrolled over a period of eight years and treated with standard doses of Chloroquine (CQ), Sulphadoxine-Pyrimethamine (SP) or Amodiaquine (AQ) given alone or in combination with artemisinin. Each patient was followed up for at least 14 days. Age, axillary temperature, parasite density and gametocytaemia were assessed for their potential association with delay in PC and treatment outcomes. Filter-paper blood samples were collected from some of the children (n=148) before treatment and on days 1-7, 14, 28 and 35 after treatment for determination of CQ and sulphadoxine concentrations. In another subset of patients (n=7), treated with amodiaquine, blood and saliva samples were collected over 35 days. High performance liquid chromatographic techniques were used to determine concentrations of sulphadoxine in whole blood as well as AQ and Desethyl amodiaquine (DEAQ) in saliva. Mean maximum drug concentration (Cmax), half-life (t1/2) and area under concentration-time curve (AUC0-28d) were assessed for their association and predictive value for treatment outcomes. Data were analyzed using descriptive statistics, ANOVA, Chi-square, Students’ t-test, Kruskal-Wallis and multiple regressions at p = 0.05. Age ≤ 2 years (Adjusted odds ratio [AOR] = 2.13), presence of fever (AOR = 1.33) and parasitaemia > 50,000/µl (AOR = 2.21) at enrolment were independent risk 3 factors for delay in PC, while a body temperature >38OC and parasitaemia >20,000/µl were predictors a day after treatment regardless of the drug used. Day 3 concentration ≤ 1750ng/ml and AUC0-28d ≤ 950ng/ml.h were associated with chloroquine treatment failure. In a multivariate analysis, a terminal elimination t½ ≤ 220h (AOR = 0.28) and AUC0-28d ≤ 950ng/ml.h (AOR = 4.12) were identified as independent pharmacokinetic predictors of chloroquine treatment failure. Age stratified analysis showed that SDX concentrations were significantly higher in children > 5years compared to children <5years: Cmax; 295 vs 125µg/ml, AUC0-28d; 1562 vs 812µg/ml.d. In patients who received AQ, there was a rapid conversion of AQ to DEAQ, which was detectable in plasma and saliva within 40 minutes of administration. The mean day 7 concentration of DEAQ was significantly higher in plasma than in saliva (247.8 vs 125.1ng/ml). The t1/2 of DEAQ were similar in plasma (167.25±43.4h) and saliva (146.12±17.2h). The decline phases of DEAQ in saliva concentration-time curves were approximately similar to that in plasma. Delay in parasite clearance is specific and related to drug resistance. In addition pharmacokinetic variability of sulphadoxine in children has potential impact on dosage regimen and treatment outcome. 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

EVALUATION OF THE ANTIPSYCHOTIC PROPERTY OF MORIN AND ITS MECHANISMS OF ACTION IN EXPERIMENTAL MICE

Fri, 01 Jun 2018 00:00:00 GMT

Title: EVALUATION OF THE ANTIPSYCHOTIC 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 fulfillment of the requirements for the Degree of DOCTOR OF PHILOSOPHY of the UNIVERSITY OF IBADAN

Endocrine disruptors-arsenic, cadmium and lead in pre and postmenopausal black women with breast cancer

Sun, 01 Jan 2017 00:00:00 GMT

Title: Endocrine disruptors-arsenic, cadmium and lead in pre and postmenopausal black women with breast cancer Authors: Ajayi, O. O.; Charles-Davies, M. A.; Anetor, J. I.; Ademola, A. F. Abstract: Background: The involvement of toxic metals in adiposity has been suggested to be contributory to the high incidence of breast cancer, particularly in sub-Saharan Africa. This study is aimed at evaluating serum arsenic, cadmium and lead in relation to adiposity and blood pressure in Nigerian women with breast cancer. Methodology: The study comprised 85 women newly diagnosed with breast cancer pre-therapy (cases) matched with 84 apparently healthy women without breast cancer (controls) according to age and menstrual phase. Arsenic (As), cadmium (Cd) and Lead (Pb) levels were determined by atomic absorption spectrophotometry. Blood pressure and anthropometry were determined by standard methods. Data analysed by Student’s t-test and Pearson correlation coefficient were considered statistically significant at p<0.05. Results: Cd and Pb levels were significantly higher in cases, compared with controls (p<0.05). Waist circumference (WC), hip circumference (HC), weight, height, waist hip ratio (WHR), waist height ratio (WHtR) were significantly higher in cases compared with controls (p<0.05). Cadmium positively correlated with diastolic blood pressure while FT4 inversely correlated with arsenic in the cases (p<0.05). Conclusion: Observations in this study suggest the involvement of these toxic metals in adiposity which could be involved in breast carcinogenesis.