Date of Award

1998

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

Keywords

Chemistry, Biochemistry.

Rights

CC BY-NC-ND 4.0

Abstract

Perhaps the most challenging problem of nitric oxide-photodynamic therapy is the choice of an appropriate nitric oxide (NO) carrier. In the first part of this study, two NO carriers were investigated: Metallothionein and dendrimers. Metallothionein has the ability to carry eighteen nitric oxide molecules, whereas each dendrimer upon conjugation to thiols, has the ability to carry up to ten nitric oxide molecules. In testing both carriers, the cytotoxic potential of this light-activated nitric oxide generating system was demonstrated towards human colon adenocarcinoma cells (SW 948) in culture. 98% cell death occurred in light irradiated samples after a 72 h incubation period. Since nitric oxide-photodynamic therapy has proven to be toxic towards tumor cells in culture, the photodynamic effects of S-nitrosoglutathione and aminolevulinic acid were tested on ocular fibrosis in vitro to improve glaucoma filtration surgery. Upon investigation of the mode of cell death post S-nitrosoglutathione photodynamic treatment, a direct evidence of necrotic mode occurred. In the second part of this study, nitric oxide synthase (NOS) isoform-dependent peroxynitrite production was monitored in control and diabetic platelets. Using dichlorofluorescein for the detection of peroxynitrite, and in the presence of extracellular L-arginine, diabetic platelets displayed a ∼5-fold higher fluorescent level in comparison to controls. Upon using a NOS inhibitor, the dichlorofluorescein fluorescence was nearly abolished. Furthermore, immunoblot analysis of intraplatelet proteins indicated that the induced (NOS) is detected in diabetic platelets and not in controls. The change in the intraplatelet nitric oxide isozymes was also investigated in hyperlipidemic subjects treated with the hypercholesterolemic drug Atorvastatin in an 8-week study. The results correlated with cholesterol, low-density lipoprotein, hig-density lipoprotein and triglycerides indicated that with Atrovastatin endothelial NOS levels increased, as cholesterol levels decreased. Interestingly, levels of nitrotyrosylated platelet proteins, an indication of peroxynitrite damage, decreased as endothelial NOS increased in presence of the drug. Another potential benefit of Atorvastatin was the fact that the level of intraplatelet induced NOS was lowered by this drug.Dept. of Chemistry and Biochemistry. Paper copy at Leddy Library: Theses & Major Papers - Basement, West Bldg. / Call Number: Thesis1998 .T36. Source: Dissertation Abstracts International, Volume: 61-09, Section: B, page: 4707. Thesis (Ph.D.)--University of Windsor (Canada), 1998.

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