Major depression is a highly prevalent mood disorder with chronic debilitating effects. Additional to a rising rate in incidence, depression is highly co–morbid with other psychiatric disorders, but also chronic cardiometabolic illnesses that present with an inflammatory component. The exact aetiology of depression is still unknown, being multifactorial in its possible aetiology. Various hypotheses have attempted to shed light on both endogenous and exogenous risk factors as well as the underlying pathology that may lead to the development of the disease. This has led to a wide range of mediators being implicated, including biogenic amines, the HPA–axis, neurotrophic factors, inflammatory agents, the cholinergic system and circadian rhythm, to name a few. The mechanisms of action of current treatment strategies, except for a few atypical and novel treatment approaches, are limited to interactions with monoamines and are at best only 65% effective. Many of these are also plagued by troubling side–effects, relapse and recurrence. It has therefore become imperative to explore novel targets for the treatment of depression that may produce more rapid, robust and lasting antidepressant effects with a less daunting side–effect profile. The strong co–morbidity between depression and various cardiometabolic disorders, including cardiovascular disease, atherosclerosis, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has led to the proposal that a metabolic disturbance may be a vital component that drives inflammatory and immunological dysfunction in depression. Supporting of this is evidence for a role of inflammatory cytokines and neurotrophic factors in the pathogenesis of depression. It has also been demonstrated that a link exists between insulin– and nitric oxide (NO)– mediated pathways in the brain, which further highlights the role of oxidative stress and cell damage. Furthermore, evidence supports a role for oxidative stress and NO in T2DM and/or insulin resistance. Insulin has also been implicated in various physiological processes in the central nervous system (CNS) and may also influence the release and reuptake of neurotransmitters. Preclinical and clinical evidence has provided support for the antidepressant–like effects of insulin–sensitizing peroxisome proliferator activated receptor (PPAR)– agonists, such as rosiglitazone and pioglitazone. In preclinical studies, however, these effects are limited to acute treatment with pioglitazone or sub–chronic (5 days) treatment with rosiglitazone. It is well–recognized that such findings need to be confirmed by chronic treatment paradigms. The aim of the current study was therefore to further investigate the proposed antidepressant–like effects of pioglitazone in a genetic animal model of depression, the Flinders sensitive line (FSL) rat, using a chronic treatment protocol. The FSL rat model was reaffirmed as presenting with inherent depressive–like behaviour compared to its more resilient counterpart, the Flinders resistant line (FRL) rat. Moreover, imipramine demonstrated a robust and reliable antidepressant–like effect in these animals using the forced swim test (FST), thus confirming the face and predictive validity of the FSL rat model for depression. In contrast to previous preclinical studies, acute dose–ranging studies with pioglitazone in Sprague Dawley rats delivered no significant anti–immobility effects in the FST, whereas results similar to that seen in the dose–ranging studies were observed following chronic treatment using FSL rats. Since altered pharmacokinetics could possibly influence the drug’s performance, another route of administration, viz. the subcutaneous route, was utilized as an additional measure to exclude this possibility. The results of the subcutaneous study, however, were congruent with that observed after oral treatment. In order to confirm an association between altered insulin sensitivity and antidepressant action and demonstration by recent studies that thiazolidinediones may augment the efficacy of existing antidepressants, we therefore investigated whether concomitant treatment with gliclazide (an insulin releaser and insulin desensitizer) or pioglitazone (an insulin sensitizer) may alter the antidepressant–like effects evoked by chronic treatment with imipramine. Pioglitazone did not positively or negatively affect the antidepressant effect of imipramine, although gliclazide tended to decrease the anti–immobility effects induced by this antidepressant. Taken together and considering the current available literature, this finding supports evidence linking the insulin–PPAR pathway to depression. However, further explorative studies are required to delineate the role of insulin sensitivity and glucose homeostasis in depression and antidepressant response. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.

Major depression is a highly prevalent mood disorder with chronic debilitating effects. Additional to a rising rate in incidence, depression is highly co–morbid with other psychiatric disorders, but also chronic cardiometabolic illnesses that present with an inflammatory component. The exact aetiology of depression is still unknown, being multifactorial in its possible aetiology. Various hypotheses have attempted to shed light on both endogenous and exogenous risk factors as well as the underlying pathology that may lead to the development of the disease. This has led to a wide range of mediators being implicated, including biogenic amines, the HPA–axis, neurotrophic factors, inflammatory agents, the cholinergic system and circadian rhythm, to name a few. The mechanisms of action of current treatment strategies, except for a few atypical and novel treatment approaches, are limited to interactions with monoamines and are at best only 65% effective. Many of these are also plagued by troubling side–effects, relapse and recurrence. It has therefore become imperative to explore novel targets for the treatment of depression that may produce more rapid, robust and lasting antidepressant effects with a less daunting side–effect profile. The strong co–morbidity between depression and various cardiometabolic disorders, including cardiovascular disease, atherosclerosis, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has led to the proposal that a metabolic disturbance may be a vital component that drives inflammatory and immunological dysfunction in depression. Supporting of this is evidence for a role of inflammatory cytokines and neurotrophic factors in the pathogenesis of depression. It has also been demonstrated that a link exists between insulin– and nitric oxide (NO)– mediated pathways in the brain, which further highlights the role of oxidative stress and cell damage. Furthermore, evidence supports a role for oxidative stress and NO in T2DM and/or insulin resistance. Insulin has also been implicated in various physiological processes in the central nervous system (CNS) and may also influence the release and reuptake of neurotransmitters. Preclinical and clinical evidence has provided support for the antidepressant–like effects of insulin–sensitizing peroxisome proliferator activated receptor (PPAR)– agonists, such as rosiglitazone and pioglitazone. In preclinical studies, however, these effects are limited to acute treatment with pioglitazone or sub–chronic (5 days) treatment with rosiglitazone. It is well–recognized that such findings need to be confirmed by chronic treatment paradigms. The aim of the current study was therefore to further investigate the proposed antidepressant–like effects of pioglitazone in a genetic animal model of depression, the Flinders sensitive line (FSL) rat, using a chronic treatment protocol. The FSL rat model was reaffirmed as presenting with inherent depressive–like behaviour compared to its more resilient counterpart, the Flinders resistant line (FRL) rat. Moreover, imipramine demonstrated a robust and reliable antidepressant–like effect in these animals using the forced swim test (FST), thus confirming the face and predictive validity of the FSL rat model for depression. In contrast to previous preclinical studies, acute dose–ranging studies with pioglitazone in Sprague Dawley rats delivered no significant anti–immobility effects in the FST, whereas results similar to that seen in the dose–ranging studies were observed following chronic treatment using FSL rats. Since altered pharmacokinetics could possibly influence the drug’s performance, another route of administration, viz. the subcutaneous route, was utilized as an additional measure to exclude this possibility. The results of the subcutaneous study, however, were congruent with that observed after oral treatment. In order to confirm an association between altered insulin sensitivity and antidepressant action and demonstration by recent studies that thiazolidinediones may augment the efficacy of existing antidepressants, we therefore investigated whether concomitant treatment with gliclazide (an insulin releaser and insulin desensitizer) or pioglitazone (an insulin sensitizer) may alter the antidepressant–like effects evoked by chronic treatment with imipramine. Pioglitazone did not positively or negatively affect the antidepressant effect of imipramine, although gliclazide tended to decrease the anti–immobility effects induced by this antidepressant. Taken together and considering the current available literature, this finding supports evidence linking the insulin–PPAR pathway to depression. However, further explorative studies are required to delineate the role of insulin sensitivity and glucose homeostasis in depression and antidepressant response. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.

The Ceratium species occurring in the Vaal River since 2000, was identified as Ceratium hirundinella (O.F. Müller) Dujardin as proposed by Van Ginkel et al (2001). Ceratium hirundinella is known to cause problems in drinking water purification and has been penetrating into the final drinking water of Rand Water since 2006. Ceratium hirundinella is associated with many other water purification problems such as disrupting of the coagulation and flocculation processes, blocking of sand filters and algal penetration into the drinking water. Ceratium hirundinella also produce fishy taste and odorous compounds and causes discolouration of the water. The aims of this study were to determine the main environmental factors which are associated with the bloom formation of C. hirundinella in the source water and to investigate the influence of C. hirundinella on the production of potable water. In order to optimise treatment processes and resolve problems associated with high C. hirundinella concentrations during the production of potable water, jar testing and chlorine exposure experiments were performed. Multivariate statistical analyses were performed to determine the main environmental variables behind C. hirundinella blooms. Ten years data (2000 - 2009) from the sampling point C–VRB5T in the Vaal River, (5 km upstream from the Barrage weir) were used for this investigation, because C. hirundinella occurred there frequently during the ten year period. In this study, it was found that C. hirundinella was favoured by high pH, Chemical Oxygen Demand (COD), orthophoshapte (PO4), and silica concentrations, as well as low turbidity and low dissolved inorganic nitrogen (DIN) concentrations. No correlation was found between C. hirundinella and temperature, suggesting that this alga does not occur during periods of extreme warm or extreme cold conditions, but most probably during autumn and spring. The results of the multivariate statistical analysis performed with historical data from Vaalkop dam, indicate that the dinoflagellate C. hirundinella seems to be favoured by low temperature and turbidity, and high DIN, Fe, Methyl–orange alkalinity, Cd, PO4, Conductivity, pH, hardness and SO4 concentrations. In order to optimise treatment processes such as coagulation, flocculation and sedimentation, jar testing experiments were performed to investigate different coagulant chemicals namely: cationic poly–electrolyte only, cationic poly–electrolyte in combination with slaked lime (CaO) and CaO in combination with activated silica. Water from four different sampling localities were chosen to perform the different jar testing experiments: 1) sampling point M–FOREBAY (in the Forebay, connecting the canal to the Zuikerbosch Purification plant) near Vereeniging due to its proximity to the Zuikerbosch treatment plant, 2) M–CANAL_VD (upstream from the inflow of the recovered water from Panfontein) to determine the influence of (if any) the recovered water from Panfontein on Forebay source water, 3) source water from Vaalkop Dam (M–RAW_VAALKOP) and 4) source water from Rietvlei Dam (water from both Vaalkop and Rietvlei Dams contained high concentrations of C. hirundinella at that time of sampling) to determine which coagulant chemical is the most effective in removing high concentrations of C. hirundinella cells during the production of drinking water. The jar testing experiments with Vaalkop Dam and Rietvlei Dam source water (rich with C. hirundinella) indicated that using cationic poly–electrolyte alone did not remove high concentrations of C. hirundinella efficiently. However, when CaO (in combination with cationic poly–electrolyte or activated silica) were dosed to Vaalkop Dam source water a significant decrease of C. hirundinella concentration was observed. This indicates that the C. hirundinella cells were “shocked or stressed” when exposed to the high pH of the CaO, rendering it immobile and thereby enhancing the coagulation and flocculation process. However, when 10 mg/L CaO in combination with poly–electrolyte was dosed to Rietvlei Dam source water the turbidity and chlorophyll–665 results indicated that this coagulant chemical procedure was ineffective in removing algal material from the source water. The jar testing experiments using the cationic poly–electrolyte alone or cationic poly–electrolyte in combination with CaO on M–FOREBAY and M–CANAL_VD source water, showed a decrease in turbidity, chlorophyll–665 concentration, and total algal biomass, with an increase of coagulant chemical. When CaO in combination with activated silica was dosed, the inherent turbidity of the lime increased the turbidity of the Vaalkop Dam, M–FOREBAY and M–CANAL_VD source water to such an extent that it affected coagulation negatively, resulting in high turbidity values in the supernatant. Regardless of the turbidity values, the chlorophyll–665 concentration and total algal biomass (C. hirundinella specifically in Vaalkop Dam source water) decreased significantly when CaO was dosed in combination with activated silica. Therefore it was concluded that a cationic poly–electrolyte alone is a good coagulant chemical for the removal of turbidity, but when high algal biomass occur in the source water it is essential to add CaO to “stress” or “shock” the algae for the effective removal thereof. However, when CaO in combination with activated silica was dosed to Rietvlei Dam source water a decrease in turbidity and chlorophyll–665 concentration was found with an increasing coagulant chemical concentration. These results confirm the fact that coagulant chemicals may perform differently during different periods of the year when water chemistry changes and that certain coagulant chemicals may never be suitable to use for certain source waters. For the effective removal of algae during water purification, it is recommended that cationic poly–electrolyte in combination with CaO are used as coagulant chemical at the Zuikerbosch Water Purification Plant. Turbidity is not a good indication of algal removal efficiency during jar testing experiments. If problems with high algal concentrations in the source water are experienced it is advisable to also determine the chlorophyll–665 concentrations of the supernatant water during the regular jar testing experiments, since it will give a better indication of algal removal. Chlorine exposure experiments were performed on water from Vaalkop Dam (M–RAW_VAALKOP) and Rietvlei Dam source water, to determine the possibility of implementing pre– or intermediate chlorination with the aim to render the cells immobile for more effective coagulation. The chlorine exposure experiments with Vaalkop Dam and Rietvlei Dam source water showed similar results. The chlorine concentration to be dosed as part of pre– or intermediate chlorination will differ for each type of source water as the chemical and biological composition of each water body are unique. When the effect of chlorine on the freshwater dinoflagellate C. hirundinella was investigated, it was found that the effective chlorine concentration where 50 % of Ceratium cells were rendered immobile (EC50) was approximately 1.16 mg/L for Vaalkop Dam source water. For the source water sampled from Rietvlei Dam, it was found that the EC50 was at approximately 0.87 mg/L. Results of analyses to determine the organic compounds in the water after chlorination revealed that an increase in chlorine concentration resulted in increase in total organic carbon concentration (TOC), as well as a slight increase in MIB and trihalomethanes (CHCl3). Pre– or intermediate chlorination seem to be an effective treatment option for the dinoflagellate C. hirundinella to be rendered immobile and thereby assisting in its coagulation process. The use of pre– or intermediate chlorination to effectively treat source waters containing high concentrations of C. hirundinella is a viable option to consider. However, the organic compounds in the water should be monitored and the EC50 value for each source water composition should be determined carefully as to restrict cell lysis and subsequent release of organic compounds into the water. / Thesis (M.Sc. (Environmental Science))--North-West University, Potchefstroom Campus, 2012.

The Ceratium species occurring in the Vaal River since 2000, was identified as Ceratium hirundinella (O.F. Müller) Dujardin as proposed by Van Ginkel et al (2001). Ceratium hirundinella is known to cause problems in drinking water purification and has been penetrating into the final drinking water of Rand Water since 2006. Ceratium hirundinella is associated with many other water purification problems such as disrupting of the coagulation and flocculation processes, blocking of sand filters and algal penetration into the drinking water. Ceratium hirundinella also produce fishy taste and odorous compounds and causes discolouration of the water. The aims of this study were to determine the main environmental factors which are associated with the bloom formation of C. hirundinella in the source water and to investigate the influence of C. hirundinella on the production of potable water. In order to optimise treatment processes and resolve problems associated with high C. hirundinella concentrations during the production of potable water, jar testing and chlorine exposure experiments were performed. Multivariate statistical analyses were performed to determine the main environmental variables behind C. hirundinella blooms. Ten years data (2000 - 2009) from the sampling point C–VRB5T in the Vaal River, (5 km upstream from the Barrage weir) were used for this investigation, because C. hirundinella occurred there frequently during the ten year period. In this study, it was found that C. hirundinella was favoured by high pH, Chemical Oxygen Demand (COD), orthophoshapte (PO4), and silica concentrations, as well as low turbidity and low dissolved inorganic nitrogen (DIN) concentrations. No correlation was found between C. hirundinella and temperature, suggesting that this alga does not occur during periods of extreme warm or extreme cold conditions, but most probably during autumn and spring. The results of the multivariate statistical analysis performed with historical data from Vaalkop dam, indicate that the dinoflagellate C. hirundinella seems to be favoured by low temperature and turbidity, and high DIN, Fe, Methyl–orange alkalinity, Cd, PO4, Conductivity, pH, hardness and SO4 concentrations. In order to optimise treatment processes such as coagulation, flocculation and sedimentation, jar testing experiments were performed to investigate different coagulant chemicals namely: cationic poly–electrolyte only, cationic poly–electrolyte in combination with slaked lime (CaO) and CaO in combination with activated silica. Water from four different sampling localities were chosen to perform the different jar testing experiments: 1) sampling point M–FOREBAY (in the Forebay, connecting the canal to the Zuikerbosch Purification plant) near Vereeniging due to its proximity to the Zuikerbosch treatment plant, 2) M–CANAL_VD (upstream from the inflow of the recovered water from Panfontein) to determine the influence of (if any) the recovered water from Panfontein on Forebay source water, 3) source water from Vaalkop Dam (M–RAW_VAALKOP) and 4) source water from Rietvlei Dam (water from both Vaalkop and Rietvlei Dams contained high concentrations of C. hirundinella at that time of sampling) to determine which coagulant chemical is the most effective in removing high concentrations of C. hirundinella cells during the production of drinking water. The jar testing experiments with Vaalkop Dam and Rietvlei Dam source water (rich with C. hirundinella) indicated that using cationic poly–electrolyte alone did not remove high concentrations of C. hirundinella efficiently. However, when CaO (in combination with cationic poly–electrolyte or activated silica) were dosed to Vaalkop Dam source water a significant decrease of C. hirundinella concentration was observed. This indicates that the C. hirundinella cells were “shocked or stressed” when exposed to the high pH of the CaO, rendering it immobile and thereby enhancing the coagulation and flocculation process. However, when 10 mg/L CaO in combination with poly–electrolyte was dosed to Rietvlei Dam source water the turbidity and chlorophyll–665 results indicated that this coagulant chemical procedure was ineffective in removing algal material from the source water. The jar testing experiments using the cationic poly–electrolyte alone or cationic poly–electrolyte in combination with CaO on M–FOREBAY and M–CANAL_VD source water, showed a decrease in turbidity, chlorophyll–665 concentration, and total algal biomass, with an increase of coagulant chemical. When CaO in combination with activated silica was dosed, the inherent turbidity of the lime increased the turbidity of the Vaalkop Dam, M–FOREBAY and M–CANAL_VD source water to such an extent that it affected coagulation negatively, resulting in high turbidity values in the supernatant. Regardless of the turbidity values, the chlorophyll–665 concentration and total algal biomass (C. hirundinella specifically in Vaalkop Dam source water) decreased significantly when CaO was dosed in combination with activated silica. Therefore it was concluded that a cationic poly–electrolyte alone is a good coagulant chemical for the removal of turbidity, but when high algal biomass occur in the source water it is essential to add CaO to “stress” or “shock” the algae for the effective removal thereof. However, when CaO in combination with activated silica was dosed to Rietvlei Dam source water a decrease in turbidity and chlorophyll–665 concentration was found with an increasing coagulant chemical concentration. These results confirm the fact that coagulant chemicals may perform differently during different periods of the year when water chemistry changes and that certain coagulant chemicals may never be suitable to use for certain source waters. For the effective removal of algae during water purification, it is recommended that cationic poly–electrolyte in combination with CaO are used as coagulant chemical at the Zuikerbosch Water Purification Plant. Turbidity is not a good indication of algal removal efficiency during jar testing experiments. If problems with high algal concentrations in the source water are experienced it is advisable to also determine the chlorophyll–665 concentrations of the supernatant water during the regular jar testing experiments, since it will give a better indication of algal removal. Chlorine exposure experiments were performed on water from Vaalkop Dam (M–RAW_VAALKOP) and Rietvlei Dam source water, to determine the possibility of implementing pre– or intermediate chlorination with the aim to render the cells immobile for more effective coagulation. The chlorine exposure experiments with Vaalkop Dam and Rietvlei Dam source water showed similar results. The chlorine concentration to be dosed as part of pre– or intermediate chlorination will differ for each type of source water as the chemical and biological composition of each water body are unique. When the effect of chlorine on the freshwater dinoflagellate C. hirundinella was investigated, it was found that the effective chlorine concentration where 50 % of Ceratium cells were rendered immobile (EC50) was approximately 1.16 mg/L for Vaalkop Dam source water. For the source water sampled from Rietvlei Dam, it was found that the EC50 was at approximately 0.87 mg/L. Results of analyses to determine the organic compounds in the water after chlorination revealed that an increase in chlorine concentration resulted in increase in total organic carbon concentration (TOC), as well as a slight increase in MIB and trihalomethanes (CHCl3). Pre– or intermediate chlorination seem to be an effective treatment option for the dinoflagellate C. hirundinella to be rendered immobile and thereby assisting in its coagulation process. The use of pre– or intermediate chlorination to effectively treat source waters containing high concentrations of C. hirundinella is a viable option to consider. However, the organic compounds in the water should be monitored and the EC50 value for each source water composition should be determined carefully as to restrict cell lysis and subsequent release of organic compounds into the water. / Thesis (M.Sc. (Environmental Science))--North-West University, Potchefstroom Campus, 2012.