Cyclosporine A induced alterations to endothelial function and erythrocyte and plasma redox balande, and the benefits of antioxidant supplementation

Lexis, Louise A (2005). Cyclosporine A induced alterations to endothelial function and erythrocyte and plasma redox balande, and the benefits of antioxidant supplementation PhD Thesis, School of Human Movement Studies, The University of Queensland.

       
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Author Lexis, Louise A
Thesis Title Cyclosporine A induced alterations to endothelial function and erythrocyte and plasma redox balande, and the benefits of antioxidant supplementation
School, Centre or Institute School of Human Movement Studies
Institution The University of Queensland
Publication date 2005
Thesis type PhD Thesis
Supervisor Jeff Coombes
Ross Richards
Lindsay Brown
Total pages 184
Collection year 2005
Language eng
Subjects 1106 Human Movement and Sports Science
1116 Medical Physiology
111603 Systems Physiology
111601 Cell Physiology
111602 Human Biophysics
Formatted abstract

Cardiovascular disease is significantly increased in organ transplant recipients and remains the largest single factor limiting long term survival in these patients. In the general population, inverse associations have been found between cardiovascular disease and both erythrocyte and plasma antioxidants. Studies have also shown that endothelial dysfunction is an independent predictor of cardiovascular disease, and convincing evidence is accumulating to implicate oxidative stress in its pathogenesis and progression. Recent studies have shown altered redox balance in the plasma and erythrocytes of transplant recipients, as well as impaired endothelial function. Cyclosporine A (cyclosporine) is the most common immunosuppressant administered to prevent organ rejection, and evidence suggests that this drug increases reactive oxygen species formation and may therefore be responsible for the altered blood redox balance and endothelial dysfunction observed in human transplant recipients. Indeed, it has been well established in animal models that cyclosporine induces endothelial dysfunction. 

 

The initial aim of this thesis was to determine if cyclosporine administration alters erythrocyte and plasma redox balance. After the first two studies showed that cyclosporine administration effects erythrocyte and plasma redox balance, a final study was designed to determine the effects of dietary supplementation with α-tocopherol and α-lipoic acid on 1) cyclosporine induced alterations to erythrocyte and plasma redox balance, and, 2) cyclosporine induced endothelial dysfunction. 

 

The first chapter provides an introduction to the thesis and begins with a summary of key information fundamental to the rationale of the thesis studies. Essential background information on the fundamentals of endothelial function and oxidative stress is then presented, followed by the specific justification, aims, and hypotheses of the thesis studies. Chapter 2 provides a review of literature which includes the results of original investigations pertinent to the aims of the thesis. The three scientific studies are presented in Chapters 3, 4, and 5. 

 

The aim of Study 1, presented in Chapter 3, was to determine if cyclosporine administration for 18 days alters erythrocyte redox balance and decreases plasma antioxidant capacity. Upon completion of the cyclosporine administration protocol, plasma and erythrocytes were analysed for antioxidants and markers of oxidative stress. Plasma was analysed for total antioxidant capacity, α -tocopherol, and malondialdehyde. Erythrocytes were analysed for α -tocopherol, malondialdehyde, and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase. Cyclosporine administration altered erythrocyte redox balance, decreased plasma antioxidant capacity, and increased plasma oxidative stress. This study has been accepted for publication in the journal Redox Report. 

 

The aim of Study 2, presented in Chapter 4, was to extend the findings of Study 1 by investigating the effect of cyclosporine administration on erythrocyte and plasma redox balance for more acute time periods than 18 days. Cyclosporine treated animals received the drug for either 7 days or a single dose. After cyclosporine treatment, plasma and erythrocytes were analysed for antioxidants and markers of oxidative stress. Plasma was analysed for total antioxidant capacity, α -tocopherol, and malondialdehyde. Erythrocytes were analysed for α -tocopherol, glutathione, malondialdehyde, methaemoglobin, and the activities superoxide dismutase, catalase, glutathione peroxidase, and glucose-6- phosphate dehydrogenase. Cyclosporine administration for 7 days altered erythrocyte redox balance and increased plasma oxidative stress, however, a single dose of cyclosporine had no effect on any of the variables measured. Data from this study was presented at the American Society of Nephrology Annual Meeting in St Louis, Missouri, 2004. This study has also been submitted to the journal Basic and Clinical Pharmacology and Toxicology for publication. 

 

Chapter 5 provides details of Study 3. Rats were supplemented with the antioxidant combination of α -tocopherol and α -lipoic acid for 8 weeks prior to being administered with cyclosporine for 10 days. After completion of the drug treatment, plasma and erythrocytes were analysed for antioxidants and markers of oxidative stress. Plasma was analysed for total antioxidant capacity, α -tocopherol, and malondialdehyde. Erythrocytes were analysed for α -tocopherol, glutathione, malondialdehyde, methaemoglobin, and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glucose-6- phosphate dehydrogenase. Endothelial function of the thoracic aorta was determined in vitro. Dietary supplementation with α -tocopherol and α -lipoic acid prevented the cyclosporine induced decrease in erythrocyte superoxide dismutase activity and attenuated cyclosporine impaired vascular dysfunction. This study has been submitted to the journal Cardiovascular Research for publication. 

 

A discussion of the major findings of this thesis, overall conclusions, and implications for future research are presented in Chapter 6. 

 

In summary, cyclosporine administration alters redox balance in erythrocytes and plasma in the rat model. Cyclosporine therapy may therefore be responsible for the altered redox balance observed in the erythrocytes and plasma of organ transplant recipients. Dietary supplementation with α -tocopherol and α -lipoic acid prevented the cyclosporine induced decrease in erythrocyte superoxide dismutase activity, and attenuated cyclosporine impaired vascular dysfunction. Although the relevance of these findings to the clinical setting is yet to be determined, the results suggest that antioxidant supplementation with α -tocopherol and α -lipoic acid may be beneficial in the management of cyclosporine dependent patients. 

Keyword Cyclosporine -- Physiological effect
Vascular endothelium -- Physiology
Transplantation of organs, tissues, etc. -- Physiological effect

Document type: Thesis
Collection: UQ Theses (RHD) - UQ staff and students only
 
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