Theses and Dissertation collection from the College of Health Sciences

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    EFFECTS OF CARVEDILOL ON STREPTOZOTOCIN INDUCED DIABETIC CARDIAC AUTONOMIC NEUROPATHY IN WISTAR RATS
    (UNIVERSITY OF ILORIN, 2021-05) AKINLADE, OLAWALE MATHIAS
    The prevalence of diabetic cardiac autonomic neuropathy (DCAN) is very high among patients with diabetes mellitus (DM). Despite intensive research on mechanism and treatment of DCAN, it still remains a major cause of mortality. Although carvedilol has been recommended for the treatment of heart failure, its role in the management of DCAN is yet to be established. This study investigated the effects of carvedilol on streptozotocin-induced DCAN rats. The objectives of the study were to determine the: (i) outcome of DM and DCAN induction in rats; (ii) effects of carvedilol on biochemical markers of autonomic nervous system in streptozotocin-induced DCAN rats; (iii) effects of carvedilol on heart rate variability (HRV) indices in streptozotocin-induced DCAN rats; and (iv) effects of carvedilol on cardiac histology and nerve densities (ND) in streptozotocin-induced DCAN rats. Eighty-four Wistar rats were assigned into two groups in the induction phase; type 1 DM model (single high dose Streptozotocin (STZ) at 50mg/kg body weight (bw)) and type 2 DM model (high fat diet feeding for 8 weeks, thereafter 25mg/kg bw of STZ daily for five days) respectively. In the interventional phase; each model was sub-divided into five sub-groups comprising; i) a sham control sub-group; ii) three DCAN sub-groups receiving carvedilol at 0.1, 1 and 10mg/kg bw respectively for 28 days; and iii) a DCAN control sub-group without carvedilol. Blood glucose, C-peptide, insulin, homeostatic model for assessment of insulin resistance and pancreas histology were adopted in assessing DM induction. Holter electrocardiogram was used to access HRV indices. Antioxidant markers, autonomic biomarkers, cardiac histology and ND were evaluated using standard methods. Data, expressed as means ± standard errors of mean were analysed using one way analysis of variance and Bonferonni’s Post-hoc test at p<0.05. The findings of the study were that: (i) STZ-induced DM rats had significantly (p<0.05) higher blood glucose (22.50 ± 7.53 vs. 4.68 ± 0.59 mmol/L) and lowered insulin and C-peptide. Advanced glycated end products (AGEs) (63.54 ± 2.09 vs. 23.04 ± 5.17 ng/ml and 91.61 ± 9.09 vs. 32.04 ± 6.37 ng/ml) and noradrenaline (528.21 ± 279.48 vs. 119.06 ± 57.88 pg/ml and 889.76 ± 299.48 vs. 111.56 ± 57.65 pg/ml) were significantly higher in both DM models respectively; (ii) choline acetyl tranferase (choactase) and nerve growth factor (NGF) were significantly reduced after STZ treatment; (iii) carvedilol significantly (p<0.05) increased gluthathione level, total anti-oxidant capacity, choactase activity (1.21 ± 0.04 vs. 0.71 ± 0.02 ng/ml and 1.14 ± 0.03 vs. 0.69 ± 0.02 ng/ml) and NGF whereas it reduced the AGEs and noradrenaline levels in both DM models; (iv) carvedilol significantly (p<0.05) increased high frequency power spectral (14,096.7 ± 238.5 vs. 5,403.5 ± 125.7 ms2 and 8,123.9 ± 167.3 vs. 3,057.8 ± 101.8 ms2 respectively) and other autonomic heart rate variables but reduced the low frequency power spectral in both models of DM; and (v) carvedilol had no significant (p>0.05) effect on cardiac axonal dystrophy and cardiac ND in both models. The study concluded that carvedilol ameliorated cardiac autonomic neuropathy in both DM animal models. The study recommended multicenter randomized clinical trials to ascertain the role of carvedilol in DCAN patients.
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    CYTOKINES GENES PATTERN IN HUMAN PAPILLOMAVIRUS AND Chlamydia trachomatis CO-INFECTION AMONG WOMEN IN ILORIN, NIGERIA
    (UNIVERSITY OF ILORIN, 2019-12) OMOARE, ADESUYI AYODEJI
    Human Papillomavirus (HPV) is a common sexually transmitted pathogen. HPV infection is a mandatory but not sufficient cause of cervical cancer. However, some women infected with HPV ultimately develop the disease. Several co-factors including Chlamydia trachomatis (CT) infection and pro-inflammatory cytokines are believed to influence the clinical outcome of HPV infection. Cytokines genes are polymorphic in nature and can lead to individual variation in cytokines production. This study assessed the cytokines genes pattern in HPV and CT co-infected women in Ilorin, Nigeria. The objectives were to: (i) identify participants with abnormal changes in cells of the cervix; (ii) detect HPV DNA in the exfoliated cervical cells of participants; (iii) determine the prevalence of HPV and the proportion of high risk HPV (HRHPV) among participants; (iv) identify CT DNA and its prevalence in cervical samples of participants; (v) determine the prevalence of HPV and CT co-infection; (vi) profile the cytokines genes associated with co-infection; and (vii) assess the risk factors associated with HPV and CT co- infections. Exfoliated cervical cells from 376 women were analysed by Papanicolaou test. Deoxyribonucleic acids (DNA) was extracted from the cells and amplified by Polymerase Chain Reaction (PCR) assays. MY09/11 and GP5+/6+ primers were used for amplification of HPV DNA by nested PCR; eighteen specific type primers for HRHPV DNA were amplified by nested multiplex PCR. Cryptic Plasmid primers were used to detect CT DNA by conventional PCR. Pro-inflammatory cytokines genes [Interferon gamma (IFN-γ) and Tumour Necrosis Factor alpha (TNF-α)] and anti-inflammatory cytokines genes [Interleukin-10 (IL-10) and Tumour Growth Factor-beta (TGF-β codons 10 and 25)] were amplified with Amplification Refractory Mutation System PCR. Statistical analysis of the data was done using chi-square, student t-test (t) and multiple regressions at p< 0.05. The findings of this study were that: xxiii (i) 19 (5.1%) women had abnormal cervical cytology out of which 13 (3.5%) had Low Squamous Intra-epithelial Lesion, 4 (1.1%) had Atypical Squamous Cell of Undetermined Significance and 2 (0.5%) had High Squamous Intra-epithelial Lesion; (ii) the fragments corresponded in position to base pairs (bp) of HPV (150 and 450 bp) and HRHPV (~118-457 bp); (iii) the prevalence of HPV was 81.4%, out of which 53.5% had HRHPV genotypes with HPV 82 being the most abundant (33.5%); (iv) CT fragments appeared at 201 bp, with a prevalence of 4.5%; (v) the prevalence of co-infection was 4.0%; (vi) comparison of co-infection with single infection showed significant differences (p< 0.05) in IFN-γ, TNF-α and TGF-β10. Also, when HPV and CT single infections were compared, IFN-γ and TNF-α showed significant difference (p< 0.05); (vii) HPV and CT individual infections were associated with risk factors such as age, parity, age at sexual debut, female genital cutting and contraceptive use. The study concluded that there were significant variations in predominantly pro-inflammatory cytokine genes in relation to HPV and CT co-infected women in Ilorin. The study recommended that these gene patterns may be used as predictor of HPV disease.
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    HIPPOCAMPAL CELLULAR RESPONSES TO Datura metel ALKALOID (DATUMETINE) AND N-METHYL-D-ASPARTATE RECEPTOR INTERACTION IN C57BL/6 MICE
    (UNIVERSITY OF ILORIN, 2021-04) ISHOLA, Azeez Olakunle
    Datura metel is a plant that is used as a form of herbal treatment in Nigeria. However, its recreational abuse is increasing among Nigerian youths due to its availability. Which is worrisome because of some untoward side effects like memory loss and hallucinations in humans. This study was designed to investigatethe effects of datumetine (alkaloid) in Datura plant on hippocampal N-methyl-D-aspartate receptors (NMDAR) functions. The objectives of the study were to determinethe effects of datumetine on: (i) memory; (ii) some NMDAR signalling molecules (iii) hippocampal cellular morphology; (iv) hippocampal synapse; and (v) hippocampal electrical activity. Thirty adult male C57/BL6 mice were assigned into three groups of 10 mice each. The mice were administered dimethyl sulfoxide (DMSO/Control), 0.25mg/Kg body weight of datumetine and 1mg/Kg body weight of datumetine intraperitoneally for 14 days. Novel object recognition (NOR) and Y-maze tests were conducted on the animals on days 10 and 13 of administration to assess the level of memory. At the end of treatment, mice were euthanized in isofluorane chamber, perfused transcardially with 1X phosphate buffered solution followed by 4% paraformaldehyde (for immunofluorescence samples). Western blotting was used to assess hippocampal levels of glutamate ionotropic receptor subunit-1 (GluN1), calcium-camodulin kinase-alpha 2-subunit (CamKIIα), phosphorylated calcium-camodulin kinase-alpha-2 subunit at threonine-286 (pCamKIIα-T286), cyclic adenosine-mono-phosphate response element-binding protein (CREB) and brain-derived neurotrophic factor(BDNF) while the distribution of major neuronal subtypes, astrocytes, and microglia were expressed using immunofluorescence antibodies. Expansion and electron microscopy techniques were used to assess neural connections and synapse morphology respectively, while in vivo electrophysiology wasperformed for hippocampal electrical activity. Quantitative data were compared using analysis of variance(ANOVA) and/or unpaired t- test at significant level of p<0.05. The findings of the study were that: i. datumetine binds with NMDAR at its binding sites ii. memory index from NOR (44.31±5.86%, 45.71±7.91%) and Y-maze (53.05±1.91%, 30.53±4.47%) were significantly reduced in datumetine exposedanimals than control(86.69±8.44%, 66.86±3.53%) (F(2,12)=7.514, F(2,8)=15.96 p = 0.0077, 0.0160) iii. datumetine significantly increased hippocampal expression of GluN1 (0.0666±0.0088, 0.0987±0.0227) and CamKIIα (0.4276±0.0016, 0.2679±0.0076) than control (0.0406±0.0068, 0.1609±0.0051) (p = 0.0578, 0001) while pCamKIIαT286 (0.4062±0.0051, 0.3552±0.0171), CREB (0.2447±0.0258) and BDNF (1.1680±0.0195, 0.8741±0.0287) were significantly reduced in datumetine treated animals than control (0.4326±0.0144, 0.4615±0.0050, 1.2680±0.0337) (p = 0.00760, 0022, 0.0001), iv. increased hippocampal expression of astrocytes, microglia, glutamatergic, GABAergic, cholinergic, and dopaminergic neurons are in datumetine exposed mice.However, there was a xx reductionin expression of serotonergic neurons of datumetine exposed mice (791.6±98.2, 953.7±22.3) compared to control (1368.0±64.5) (F(2,27)=22.49, p=0.0016), v. datumetine exposure depleted neurofilament expression, arrangement and altered synaptic morphology; and vi. prolonged duration of interspike interval (2.607±0.772 s), interburst interval (16.08±2.86 s) and burst duration (0.0599±0.0093 s) were observed in datumetine treated mice than control (0.533±0.077 s, 9.265±0.86 s, 0.0464±0.0028 s) (p = 0.0007, 0.0059, 0.0880). The study concluded that datumetine increased hippocampal NMDAR activity, resulting in excitotoxicity, impairment of selected neural diffuse systems thereby leading to memory loss. The study recommended that the use of Datura metel plant be discouraged among the populace
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    HYPOTHALAMIC-PITUITARY-TESTICULAR-AXIS RESPONSE IN WISTAR RAT TREATED WITH CHLORPROMAZINE, RAUWOLFIA VOMITORIA LEAF AND COMBINATION OF RESERPINE, ASCORBATE AND ZINC
    (UNIVERSITY OF ILORIN, 2021-04) ADELEKE, OPEYEMI SAMSON
    Synthetic antipsychotic drugs have been reported to induce reproductive toxicity while psychiatric patients treated with traditionally used herb like Rauwolfia vomitoria (RV) showed no traces of reproductive toxicity. Molecular mechanisms underlying control of Hypothalamic-Pituitary-Testicular-Axis (HPTA) by synthetic and traditionally used antipsychotic drugs are poorly understood. Thus, this study aimed to compare the effects of chlorpromazine (CPZ), RV leaf extracts and combination of reserpine, ascorbic acid and zinc (RAZ) on HPT-Axis of Wistar rats. The objectives of the study were to determine: (i) histological changes in the testes and hypothalamus; (ii) gonadotropin releasing hormone (GnRH), cytokeratin-18, Bcl2 and ki-67 protein expression; (iii) expression of Cyclic-adenosine-monophosphate Responsive Element Modulator (CREM), protamine (PRM) genes in the testes (iv) andrological parameters; and (v) antioxidant status. Seventy-two male Wistar rats (weight: 180.00+4.67g) were assigned into nine groups (A-I) (n=8). Group A (control) was administered physiological saline while rats in Groups B and C received 10 and 20 mg/kg body weight (bwt) of chlorpromazine respectively. Groups D and E received 2.5 and 5 mg/kg bwt of reserpine while Groups F and G received 150 and 300 mg/kg bwt of RV leaf extract respectively. Groups H and I received (2.5:5:100) mg/kg bwt and (5:10:200) mg/kg of combination of RAZ respectively. The administration lasted for 56 days. On the 57th day, the rats were sacrificed, hypothalamus and testes were excised for histological, genes and immunohistochemical examinations while serum was used for hormonal analysis (follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, sperm count, motility and morphology) and biochemical analysis (glutathione peroxidase (Gpx), superoxide dismutase (SOD) and malondialdehyde). Data analyses were done by Analysis of Variance followed by Tukey’s post-hoc test at P<0.05 level of significant. The findings of the study were that: i. chlorpromazine and reserpine treated rats showed hypothalamic arcuate neurons and testicular germ cells degeneration; ii. chlorpromazine and reserpine treated rats showed negative immunoreactivity to GnRH and ki-67 and weak positive immunoreactivity to cytokeratin and Bcl2 proteins while vii RV and combination of RAZ treated rats showed weak positive immunoreactivity to all the proteins; iii. chlorpromazine and reserpine treated rats when compared with control and RAZ groups showed significant (p<0.001) down regulation of CREM (0.32+0.05), protamine-I (0.14+0.02) and II (0.13+0.02) genes expression; iv. serum FSH (0.19+0.03 ng/ml), LH (0.33+0.06 ng/ml), testosterone (0.15+0.02 ng/ml), percentage of normal sperm count (17.40+2.59), motility (19.60+2.86) and morphology (16.60+2.91) were significantly (p<0.001) decreased in chlorpromazine and reserpine treated animals while prolactin (0.11+0.03 ng/ml) level was significantly (p<0.01) increased when compared with control and RAZ groups; and v. serum GPx (21.00+3.50 U/L), SOD (0.54+0.12 u/mL) levels were significantly (p<0.001) reduced in chlorpromazine and reserpine treated rats while malondialdehyde (0.79+0.15) level was significantly (p<0.001) increased compared with control and RAZ groups. The study concluded that HPT-Axis was impaired by chlorpromazine and reserpine while RV and combination of RAZ (2.5:5:100) mg/kg bwt administration enhanced the axis. The study recommended that combination of RAZ should be prescribed in order to improve reproductive toxicity associated with antipsychotic drugs.
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