Sertraline is a selective serotonin reuptake inhibitor (SSRI) that is widely used for the treatment of depression and anxiety. Due to the abundant therapeutic use of sertraline, low levels have been detected in municipal wastewater effluents suggesting that aquatic organisms may be exposed. The purpose of this study was to evaluate the steroidogenic effects of sertraline on larval (FHM) and adult female fathead minnows (FFHM), Pimephales promelas. Larval FHM were exposed to 0.1, 1, and 10 µg/L sertraline for 28 days and analyzed via RT-qPCR for differential expression of 11β-Hydroxysteroid dehydrogenase (11β-HSD), 20β-Hydroxysteroid dehydrogenase (20β-HSD), aromatase (CYP19), and nuclear thyroid receptor alpha (TRα). FFHM were exposed to 3 or 10 µg/L sertraline for 7 days with the brain and ovary excised at exposure termination. Juvenile FHM exposed to 0.1 μg/L sertraline had a significant upregulation of both 20β-HSD and TRα. FFHM exposed to 10 µg/L sertraline had a significant upregulation of 11β-HSD expression in brain tissue, while no steroidogenic changes were observed in the FFHM ovary. Similarly, in FFHM brain tissue, CYP19 and 20β-HSD expression levels were significantly higher in fish exposed to 10µg/L sertraline compared to control. The significance of these findings with respect to survival, growth and reproduction are currently unknown, but represent future research needs.

Background: Pulmonary arterial hypertension (PAH) is a multifaceted disease characterized by elevated pulmonary arterial pressure, right ventricular hypertrophy, and a poor prognosis. Pathological hallmarks of PAH include pulmonary vascular remodelling, pre-capillary arterial obliteration, and plexiform lesions. Over the past 15 years, pulmonary endothelial cell (EC) apoptosis has been repeatedly implicated as a key trigger of occlusive arterial remodelling in PAH. While it has been hypothesized that pulmonary EC apoptosis gives rise to the emergence of growth-dysregulated, apoptosis- resistant ECs involved in arterial remodelling, the molecular mechanisms linking these two events has not yet been fully elucidated. Recently, our lab identified translationally controlled tumour protein (TCTP) as one of several significantly dysregulated proteins in culture-derived blood-outgrowth endothelial cells (BOECs) isolated from hereditable PAH (HPAH) patients harbouring mutations in the gene encoding for bone morphogenetic protein receptor type 2. Immunohistological analyses indicated that TCTP expression was associated with intra-luminal pulmonary ECs and inflammatory cells in the remodelled vessels of both human PAH patients and SU5416 rats. Furthermore, TCTP silencing abrogated excessive HPAH BOEC proliferation and promoted apoptosis in vitro. Hypothesis: We hypothesized that TCTP represents a central molecular mechanism linking pulmonary arterial EC damage and apoptosis to the emergence of growth- dysregulated lung vascular cells and complex arterial remodelling in PAH.Purpose: The purpose of the present thesis was to examine the effects TCTP inhibition on EC survival and TCTP abundance in vitro as well as on pulmonary hemodynamic changes and arterial remodelling in vivo using a well-validated rat model of severe PAH. Methods: Inhibition of TCTP was accomplished using two TCTP small molecule inhibitors, sertraline and thioridazine. In vitro, rat lung microvascular ECs (RLMVECs) were exposed to thioridazine and assayed for TCTP abundance, survival, and markers of apoptosis. In vivo, PAH was induced in male Sprague Dawley rats using SU5416 combined with 3 weeks of chronic hypoxia (SU/CH). After 4 weeks, right ventricle systolic pressure (RVSP) was measured by direct catheterization and osmotic pumps containing either thioridazine or sertraline were implanted subcutaneously. Following 3 weeks of small molecule delivery, RVSP was re-evaluated, cardiac function/structure was determined using transthoracic echocardiography, and histological analyses of vascular remodelling and inflammation were performed. Results: Our in vitro experiments demonstrated that thioridazine was able to significantly down-regulate TCTP levels and induce an apoptotic phenotype in RLMVECs. In the SU/CH rat model of severe PAH, both thioridazine and sertraline failed to have any effect on pulmonary hemodynamics, right ventricle structure/function, or vascular remodelling. Moreover, neither small molecule was able to detectably down-regulate TCTP levels in the lungs of SU/CH rats. Immunofluorescence staining revealed that TCTP expression occasionally corresponded with the expression of macrophage/monocyte marker CD68 in the lungs of SU/CH rats, consistent with its expression by inflammatory cells; however, no significant differences were found in adventitial cell clearance in the presence or absence of the inhibitors. Conclusions: Our findings support previous reports that thioridazine is able to significantly down-regulate TCTP and induce apoptosis in vitro. In contrast, both small molecule inhibitors failed to down-regulate lung TCTP levels or have any beneficial effects on the progression of PAH in SU/CH rats.

Analisamos o efeito do sistema serotoninérgico no desenvolvimento somático e na ontogênese de reflexos dos filhotes, cujas mães foram submetidas a tratamento farmacológico durante a prenhez. Ratas wistar prenhas foram divididas em dois grupos (N=11): Grupo AD, tratadas com água destilada, Grupo Sert, tratadas com sertralina 30mg/kg, 0,5mL/100g, s.c. Um dia após o parto 8 neonatos (4 machos e 4 fêmeas) foram mantidos com suas mães do 1º ao 21º dia pós-natal. O investigador cego avaliou o crescimento somático, características físicas e maturação de reflexos. Aos 22 e 60 dias de idade os encéfalos foram processados com técnicas de imunoistoquímica contra 5-HT. O grupo Sert, macho ou fêmea, apresentou atraso no crescimento somático e na maturação de alguns reflexos. A quantidade de neurônios 5-HT-IR foi alterada nos núcleos da rafe nos ratos aos 22 dias de idade, mas não aos 60 dias. A análise da morfometria dos neurônios 5-HT-IR, em ambas as idades estudadas, revelou alterações em sua forma. Os resultados deste estudo demonstram a ação inibitória da serotonina sobre o crescimento somático e desenvolvimento sensório-motor bem como alterações na quantidade e na forma dos neurônios 5-HT em ratos. / The aim of the present study was to investigate the effects of prenatal sertraline exposure on offspring in growth and somatic development and even in the maturation of reflex in rats. Female wistar rats were treated with sertraline (Sert, 30 mg/kg, 0,5 mL/100 g, s.c., N=11) or distilled water (Control, N=11) during the whole pregnancy. After the birth, 8 pups (4 males and 4 females) were kept in each litter during lactation. The blind investigator evaluated indicators of general body growth parameters, somatic maturation and ontogeny of reflex during the period of lactation. The central nervous system alterations were approached by 5-HT-IR using the ABC-DAB-Peroxidase techniques in animals at the 22st and 60st postnatal day. The Sert group, showed reduction on the somatic growth and on the maturation of reflexes. There was reduction in the amount of the 5-HT-IR neurons in the raphe nuclei at the 22st postnatal day, but did not change at the 60st. The morphometric analysis revealed alterations in the shape of these cells at the 22st and 60st postnatal day. An inhibitory action of the 5-HT on the somatic and sensory-motor growth in these rats was also observed. After the lactation period, the amount and shape of the 5-HT neurons were altered.

Analisamos o efeito do sistema serotoninérgico no desenvolvimento somático e na ontogênese de reflexos dos filhotes, cujas mães foram submetidas a tratamento farmacológico durante a prenhez. Ratas wistar prenhas foram divididas em dois grupos (N=11): Grupo AD, tratadas com água destilada, Grupo Sert, tratadas com sertralina 30mg/kg, 0,5mL/100g, s.c. Um dia após o parto 8 neonatos (4 machos e 4 fêmeas) foram mantidos com suas mães do 1º ao 21º dia pós-natal. O investigador cego avaliou o crescimento somático, características físicas e maturação de reflexos. Aos 22 e 60 dias de idade os encéfalos foram processados com técnicas de imunoistoquímica contra 5-HT. O grupo Sert, macho ou fêmea, apresentou atraso no crescimento somático e na maturação de alguns reflexos. A quantidade de neurônios 5-HT-IR foi alterada nos núcleos da rafe nos ratos aos 22 dias de idade, mas não aos 60 dias. A análise da morfometria dos neurônios 5-HT-IR, em ambas as idades estudadas, revelou alterações em sua forma. Os resultados deste estudo demonstram a ação inibitória da serotonina sobre o crescimento somático e desenvolvimento sensório-motor bem como alterações na quantidade e na forma dos neurônios 5-HT em ratos. / The aim of the present study was to investigate the effects of prenatal sertraline exposure on offspring in growth and somatic development and even in the maturation of reflex in rats. Female wistar rats were treated with sertraline (Sert, 30 mg/kg, 0,5 mL/100 g, s.c., N=11) or distilled water (Control, N=11) during the whole pregnancy. After the birth, 8 pups (4 males and 4 females) were kept in each litter during lactation. The blind investigator evaluated indicators of general body growth parameters, somatic maturation and ontogeny of reflex during the period of lactation. The central nervous system alterations were approached by 5-HT-IR using the ABC-DAB-Peroxidase techniques in animals at the 22st and 60st postnatal day. The Sert group, showed reduction on the somatic growth and on the maturation of reflexes. There was reduction in the amount of the 5-HT-IR neurons in the raphe nuclei at the 22st postnatal day, but did not change at the 60st. The morphometric analysis revealed alterations in the shape of these cells at the 22st and 60st postnatal day. An inhibitory action of the 5-HT on the somatic and sensory-motor growth in these rats was also observed. After the lactation period, the amount and shape of the 5-HT neurons were altered.

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To prove the post-natal depression model, the antidepressant sertraline, was assessed in rat mothers (n=14) divided into Prenatally Stressed (PS) and Non-Stressed (NS) groups. The data failed to support the hypothesis that ‘the progeny of 10mg of sertraline-treated PS mothers displayed less anxiety than the progeny of vehicle-treated PS mothers’. The forced swim test (FST) was used to examine depressive-like behaviour in mice. Barley successfully increased mobility in mice exposed to the FST. Barley was antidepressant at low doses (0.8g/kg and upwards) if used subchronic; and at high doses(6.4g/kg and 12.8g/kg) if used acutely;(n=113,56acute,57 subchronic- treated). Barley (6.4g/kg) was also able to alleviate the depressive-behaviour in mice induced by the Reserpine Test (n=114, 58 reserpinised, 56 non-reserpinised) and Social ‘Defeat’ Test (n=24, 8 vehicle undefeated, 8 barley defeated, 8 vehicle defeated mice). To confirm that the anti-depressant effects of barley(6.4g/kg) were not simply due to increased locomotor activity in the FST, an Open Field Test(OFT) was undertaken (n=14,7 vehicle, 7 barley). Barley had no effect on locomotor activity and also caused no significant changes in weight (n=16, 8vehicle, 8 barley). In mice,Barley(6.4g/kg) significantly delayed the tremorogenic effects of Physostigmine (n=18, 6 control,6 Physostigmine, 6 Physostigmine with barley); reduced bradykinesia induced by reserpine (n=18,6 control, 6 vehicle, 6 barley treated);and was analgesic in nociception tests (n =20, 5 control, 5 barley, 5 pain, 5 pain with barley). Overall, barley was seen to have many useful properties, though its effect in PND remains to be assessed. / Saudi Cultural Bureau in London; Medical Services Department of the Ministry of Interior in Riyadh, Saudi Arabia. / The full text of this thesis is embargoed indefinitely.

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Postpartum depression (PPD) is a major health problem that affects many women worldwide. In Egypt, PPD is neglected despite the expected high prevalence rate among women during the transition period after the Egyptian revolution. This research investigated the prevalence, risk factors, and interventions of postpartum depression in southern rural Egypt. Interviews were conducted with 57 participants recruited from public and private hospitals. Questionnaires and the Arabic version of the Edinburgh Postnatal Depression Scale were administered. The prevalence of PPD is 73.7%. PPD is associated with low income and age at childbirth. Most participants regarded screening mothers after childbirth for PPD as effective; in comparison to, antidepressants that were regarded by most participants as ineffective. Women in southern rural Egypt prefer high number of pregnancies, so investigating the influence of sertraline, an antidepressant medication, on female hormones becomes important. In this research, fathead minnows were exposed to 3 and 10 ppb sertraline for 7 days. Real-time Polymerase Chain Reaction was used to detect the change in gene expression of the Follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Results showed that a down regulation at the 10 ppb was evident on the LH and to a lesser extent on FSH. Our results increased levels of sertraline inhibited GnRH which influenced expression of LH and FSH.