Depressive disorders are among the most frequent psychiatric diseases in the Western world with prevalence between 9% and 18%. Poor compliance and inappropriate antidepressant discontinuation invokes long-term morbidity, and appear linked to hippocampal shrinkage. Despite major advances in pharmacological treatment of the illness over the past 3040 years, currently available agents have distinct shortfalls both in clinical efficacy and in maintenance of response. This implies a greater long-term morbidity with significant impact on the patient, the patient's family as well as economic implications to health care managers and providers. The major reason for this state of affairs is our poor understanding of the neurobiology of depression and hence, of antidepressant (AD) action. AD drugs are thus not addressing the crucial neurobiological target underlying the illness, and new strategies and treatments are urgently needed. In recent years, depression has been associated with disturbances in excitotoxic glutamatergic activity, yet this has not been systematically evaluated. While the role of neurotransmitters such as serotonin, noradrenaline and dopamine has been extensively studied, new evidence suggests a role for the unique neurotransmitter nitric oxide (NO). Nitric oxide (NO), is activated by glutamatergic systems in various limbic and other regions of the brain, and has recently also been implicated in anxiety and affective disorders. Of special interest is the putative role of NO in cellular memory, synaptic plasticity and cell survival, all-important processes in the neuropathology and neurodevelopment of depression. Recent clinical studies have provided evidence of the role of the NO-pathway in depression, while preclinical studies have demonstrated the anxiolytic and antidepressant actions of nitric oxide synthase (NOS)-inhibitors. Moreover, NO interacts with other classical transmitters that have a regulatory role on mood, particularly the monoamines, as well as glutamate and gammaaminobutyric acid (GABA). In the current study the role of the NO-cGMP pathway in AD action was investigated, after chronic imipramine (IMI) and after IMI withdrawal, using a learned helplessness paradigm. Behavioural changes, hippocampal NOS activity and cGMP accumulation was determined together with pharmacological manipulation of the NO-cGMP pathway. Chronic IMI, 15 mg/kg/day intraperitoneal (ip) administration induced a pronounced reduction in swim immobility time in the forced swim test (FST), with no effect on horizontal or vertical locomotor activity. These behavioural changes were accompanied by a significant reduction in NOS enzyme activity and cGMP accumulation. In order to confirm the involvement of the NO-cGMP pathway in the AD action of IMI, chronic (3 weeks) IMI treatment was followed by an acute withdrawal of 7 days. Acute withdrawal, after chronic IMI treatment, resulted in a significant increase in swim immobility time and an increase in NOS enzyme activity and cGMP levels. In fact, NOS activity was raised above that of control, not just higher than the effect of chronic IMI. In order to assess the possible role of the NMDA-NO-cGMP pathway in AD withdrawal, the NMDA receptor antagonist, memantine, and the NOS/guanylyl cyclase (GC) inhibitor, methylene blue (MB), were administered during the 7 day IMI withdrawal period. Memantine (5 mg/kg/d ip), during the 7 day IMI withdrawal period, significantly reversed the increase in immobility time evoked after IMI withdrawal. This was accompanied by a significant reduction in NOS enzyme activity and a tendency to decrease cGMP levels. This data confirms that the antidepressant action of IMI, as well as IMI withdrawal, is associated with actions on the NMDA-GIu-NO-cGMP pathway. Particularly. IMI withdrawal evokes an increase in glutamate activity that is responsible for NOS activation. During the 7 day IMI withdrawal period, MB (15 mg/kg/d ip) also significantly reversed the increased immobility time after IMI withdrawal and was accompanied by a tendency to decrease NOS enzyme activity and cGMP levels in the rat hippocampus, however statistical significance was not reached. Although not emphatic, this data implies a possible role of the NO-cGMP pathway in AD action and AD withdrawal. In order to determine whether the observed IMI withdrawal effects on the NO-cGMP pathway may occur through an initial destabilisation in the serotonergic system, the 5-HT2a/2c receptor antagonist, ritanserin (4 mg/kg/d ip), was administered during the IMI withdrawal period. These studies revealed that antidepressant withdrawal evokes an increase in 5-HT2-mediated activity, and that antidepressant-induced NOS activation after withdrawal has its origin in serotonergic hyperactivity. Clearly, this is supportive of a distinct relationship between the NO and serotonergic system in antidepressant response. On its own, ritanserin was found to increase NOS and cGMP levels, yet during IMI withdrawal this response was lost, suggesting that IMI withdrawal alters the response to a 5-HT2a/2c receptor antagonist, which may have major clinical implications. In conclusion, the AD action of IMI, as well as chronic IMI withdrawal, involves actions on the NO-cGMP pathway. Withdrawal of ADS is associated with a loss of AD efficacy together with an increase in release of NO and cGMP. The NMDA antagonist, memantine, and the NOS/GC inhibitor, MB, reversed these responses therefore suggesting that the NMDA-GIu-NO-cGMP pathway may be a new putative target in understanding the neurobiology of AD action. Finally, NOS activation following withdrawal suggest that inappropriate withdrawal during the treatment of depression may mediate neurodegenerative pathology observed in recurrent depression, possibly by severely increased hippocampal NOS activity which is toxic to neurons. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

The overall objective of the research presented here was to combine multiple geochemical parameters and molecular characterizations to provide a novel view of active microbial community ecology of sediments in a large-river deltaic estuary. In coastal and estuarine environments, a large portion of benthic respiration has been attributed to sulfate reduction and implicated as an important mechanism in hypoxia formation. The use of high-resolution sampling of individual sediment cores and high throughput nucleic acid extraction techniques combined with 454 FLX sequencing provided a robust understanding of the metabolically active benthic microbial community within coastal sediments. This was used to provide further understanding and show the importance of simultaneously analyzing the connectivity of sulfur and iron cycling to the structure and function of the microbial population. Although aqueous sulfide did not accumulate in the sediments of the northern Gulf of Mexico, active sulfate reduction was observed in all locations sampled. Microbial recycling and sequestration as iron sulfides prevented the release of sulfide from the sediment. Prominent differences were observed between the sample locations and with depth into the sediment column. This study emphasized the importance of combining novel molecular techniques with simultaneous traditional geochemical measurements to show the interdependence of microbiology and geochemistry. In addition, this study highlights the need to consider microbial community biogeography along with small-scale variations in geochemistry and biology that impact the overall cycling of redox elements when constructing biogeochemical models in marine sediments.

The shortcomings of current antidepressant agents prompts the design of novel multimodal antidepressants and the identification of new antidepressant targets, especially those located at sub-cellular level. Such antidepressants should possess improved response rates as well as safety profiles. Methylene blue (MB) is reported to possess diverse pharmacological actions and is attracting increasing attention for the treatment of a variety of disorders including Alzheimer’s disease, bipolar disorder, anxiety and depression. MB acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and possesses antidepressant activity in rodents. The principal goal of this study was to design a close structural analogue of MB and to evaluate the effects of these structural changes on MAO inhibition, a well-known antidepressant target. Furthermore, MAO inhibition is also responsible for cardiovascular toxicity in clinically used MAOI inhibitors. For this purpose we investigated the antidepressant properties of the synthetic MB analogue (ethyl-thioniniumchloride; ETC) as well as azure B, the major metabolite of MB, in the forced swim test (FST). ETC was synthesized with a high degree of purity from diethyl-p-phenylenediamine with 6% yield. ETC was firstly evaluated as a potential inhibitor of recombinant human MAO-A and MAO-B. Azure B and ETC were evaluated over a dosage range of 4-30 mg/kg for antidepressant-like activity in the acute FST in rats, and the results were compared to those obtained with saline, imipramine (15 mg/kg) and MB (15 mg/kg) treated rats. Locomotor activity was evaluated to ensure that changes in swim motivation are based on antidepressant response and not due to an indirect effect of the drug on locomotor activity. The results document that ETC inhibits MAO-A and MAO-B with IC50 values of 0.51 μM and 0.592 μM, respectively. Furthermore, ETC inhibits MAO-A and MAO-B reversibly, while the mode of inhibition is most likely competitive. In the acute FST, azure B and ETC were more effective than imipramine and MB in reversing immobility, without inducing locomotor effects. Azure B and ETC increased swimming behaviour during acute treatment, which is indicative of enhanced serotonergic neurotransmission. Azure B and ETC did not affect noradrenergicmediated climbing behaviour. These results suggest that azure B may be a contributor to the antidepressant effect of MB, and acts via increasing serotonergic transmission. Secondly, small structural changes made to MB do not abolish its antidepressant effect even though ETC is a less potent MAO-A inhibitor than MB. / MSc (Pharmaceutical Chemistry), North-West University, Potchefstroom Campus, 2014

Depressive disorders are among the most frequent psychiatric diseases in the Western world with prevalence between 9% and 18%. Poor compliance and inappropriate antidepressant discontinuation invokes long-term morbidity, and appear linked to hippocampal shrinkage. Despite major advances in pharmacological treatment of the illness over the past 3040 years, currently available agents have distinct shortfalls both in clinical efficacy and in maintenance of response. This implies a greater long-term morbidity with significant impact on the patient, the patient's family as well as economic implications to health care managers and providers. The major reason for this state of affairs is our poor understanding of the neurobiology of depression and hence, of antidepressant (AD) action. AD drugs are thus not addressing the crucial neurobiological target underlying the illness, and new strategies and treatments are urgently needed. In recent years, depression has been associated with disturbances in excitotoxic glutamatergic activity, yet this has not been systematically evaluated. While the role of neurotransmitters such as serotonin, noradrenaline and dopamine has been extensively studied, new evidence suggests a role for the unique neurotransmitter nitric oxide (NO). Nitric oxide (NO), is activated by glutamatergic systems in various limbic and other regions of the brain, and has recently also been implicated in anxiety and affective disorders. Of special interest is the putative role of NO in cellular memory, synaptic plasticity and cell survival, all-important processes in the neuropathology and neurodevelopment of depression. Recent clinical studies have provided evidence of the role of the NO-pathway in depression, while preclinical studies have demonstrated the anxiolytic and antidepressant actions of nitric oxide synthase (NOS)-inhibitors. Moreover, NO interacts with other classical transmitters that have a regulatory role on mood, particularly the monoamines, as well as glutamate and gammaaminobutyric acid (GABA). In the current study the role of the NO-cGMP pathway in AD action was investigated, after chronic imipramine (IMI) and after IMI withdrawal, using a learned helplessness paradigm. Behavioural changes, hippocampal NOS activity and cGMP accumulation was determined together with pharmacological manipulation of the NO-cGMP pathway. Chronic IMI, 15 mg/kg/day intraperitoneal (ip) administration induced a pronounced reduction in swim immobility time in the forced swim test (FST), with no effect on horizontal or vertical locomotor activity. These behavioural changes were accompanied by a significant reduction in NOS enzyme activity and cGMP accumulation. In order to confirm the involvement of the NO-cGMP pathway in the AD action of IMI, chronic (3 weeks) IMI treatment was followed by an acute withdrawal of 7 days. Acute withdrawal, after chronic IMI treatment, resulted in a significant increase in swim immobility time and an increase in NOS enzyme activity and cGMP levels. In fact, NOS activity was raised above that of control, not just higher than the effect of chronic IMI. In order to assess the possible role of the NMDA-NO-cGMP pathway in AD withdrawal, the NMDA receptor antagonist, memantine, and the NOS/guanylyl cyclase (GC) inhibitor, methylene blue (MB), were administered during the 7 day IMI withdrawal period. Memantine (5 mg/kg/d ip), during the 7 day IMI withdrawal period, significantly reversed the increase in immobility time evoked after IMI withdrawal. This was accompanied by a significant reduction in NOS enzyme activity and a tendency to decrease cGMP levels. This data confirms that the antidepressant action of IMI, as well as IMI withdrawal, is associated with actions on the NMDA-GIu-NO-cGMP pathway. Particularly. IMI withdrawal evokes an increase in glutamate activity that is responsible for NOS activation. During the 7 day IMI withdrawal period, MB (15 mg/kg/d ip) also significantly reversed the increased immobility time after IMI withdrawal and was accompanied by a tendency to decrease NOS enzyme activity and cGMP levels in the rat hippocampus, however statistical significance was not reached. Although not emphatic, this data implies a possible role of the NO-cGMP pathway in AD action and AD withdrawal. In order to determine whether the observed IMI withdrawal effects on the NO-cGMP pathway may occur through an initial destabilisation in the serotonergic system, the 5-HT2a/2c receptor antagonist, ritanserin (4 mg/kg/d ip), was administered during the IMI withdrawal period. These studies revealed that antidepressant withdrawal evokes an increase in 5-HT2-mediated activity, and that antidepressant-induced NOS activation after withdrawal has its origin in serotonergic hyperactivity. Clearly, this is supportive of a distinct relationship between the NO and serotonergic system in antidepressant response. On its own, ritanserin was found to increase NOS and cGMP levels, yet during IMI withdrawal this response was lost, suggesting that IMI withdrawal alters the response to a 5-HT2a/2c receptor antagonist, which may have major clinical implications. In conclusion, the AD action of IMI, as well as chronic IMI withdrawal, involves actions on the NO-cGMP pathway. Withdrawal of ADS is associated with a loss of AD efficacy together with an increase in release of NO and cGMP. The NMDA antagonist, memantine, and the NOS/GC inhibitor, MB, reversed these responses therefore suggesting that the NMDA-GIu-NO-cGMP pathway may be a new putative target in understanding the neurobiology of AD action. Finally, NOS activation following withdrawal suggest that inappropriate withdrawal during the treatment of depression may mediate neurodegenerative pathology observed in recurrent depression, possibly by severely increased hippocampal NOS activity which is toxic to neurons. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

Resuscitation from haemorrhagic shock and the subsequent circulatory arrest remains a major clinical challenge in the care of trauma patients. Numerous experimental studies in sexually mature animals have shown a gender dimorphism in response to trauma and haemorrhagic shock. The first study was designed to evaluate sex differences in outcome after resuscitation from hypovolemic circulatory arrest. We intended to examine innate sex differences, and chose to study sexually immature animals. The study showed that cerebral cortical blood flow was greater, blood-brain-barrier was better preserved and neuronal injury was smaller in female as compared to male piglets. The second study demonstrated that female sex was associated with enhanced haemodynamic response, cardioprotection, and better survival. This cardioprotective effect was observed despite comparable estradiol and testosterone levels in male and female animals, indicating an innate gender-related cardioprotection. In both studies (I and II) female sex was associated with a smaller increase in the cerebral expression of inducible and neuronal nitric oxide synthase (iNOS and nNOS). Thus in the study III we tested the hypothesis that exogenously administered 17β-estradiol (E2) could improve neurological outcome by NOS modulation. The results showed that compared with the control group, animals in the E2 group exhibited a significantly smaller increase in nNOS and iNOS expression, a smaller blood-brain-barrier disruption and a mitigated neuronal injury. There was also a significant correlation between nNOS and iNOS levels and neuronal injury. A hypothesis if female-specific cardioprotection may be attributed to a smaller NOS activity was tested in study IV. The animals received methylene blue (MB) during CPR, but were otherwise treated according to the same protocol as studies I-II. The female-specific cardioprotection could be attributed to a smaller NOS activity, but NOS inhibition with MB did not improve survival or myocardial injury, although it abated the difference between the sexes.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 440-459).

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves [158]-172).

Thesis (Ph. D.)--University of Texas at Austin, 2009. / Title from PDF title page (University of Texas Digital Repository, viewed on Sept. 9, 2009). Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2004. / Also available in print.