Date of Award
Doctor of Philosophy (PhD)
Rheumatoid arthritis is a chronic, systemic inflammatory disease. It can be treated with the gold(I) based drug, Myochrysine. Much research has been done in the past, in an attempt to elucidate the mechanism of action of this drug. To date, the mechanism remains a mystery. It is known however that Myochrysine inhibits the action of inflammatory cells. Myochrysine has been shown to inhibit phagocytosis, chemotaxis and the respiratory burst in mononuclear phagocytes and polymorphonuclear cells; T and B cell proliferation; interleukin 2 secretion from T cells; interleukin 2 receptor expression on T cells; as well as thrombin stimulated platelet aggregation and release. All of these inflammatory cell functions are mediated by a biochemical pathway involving receptor-G-protein mediated phospholipase C activation which results in Ca²⁺ mobilization and protein kinase C activation. It is proposed that Myochrysine acts to relieve rheumatoid arthritis by interfering with some point(s) in this biochemical pathway in inflammatory cells. Through the use of the platelet as a model system, it has been shown that Myochrysine inhibits the collagen, ADP, and U46619 induced platelet aggregation and serotonin release; that Myochrysine inhibits collagen induced myosin light chain and pleckstrin phosphorylation; that the inhibitory action is fast and reversible; that the inhibitory effect is not dependent on the presence of albumin; that the inhibitory effect does not involve cyclic nucleotide increases and that Myochrysine does not inhibit TPA induced pleckstrin phosphorylation or A23187 induced myosin light chain phosphorylation. More importantly, it is shown that Myochrysine inhibits platelet activation in a manner very similar to inhibition of platelet activation by other sulfhydryl reacting agents, including cell impermeant compounds. The data presented are consistent with the action of Myochrysine being at a membrane surface sulfhydryl group, most probably at a common structurally important sulfhydryl group within platelet receptors involved in the activation of the protein kinase C/Ca²⁺ mobilization pathway. Data are also presented which indicate that both the gold(I) moiety and the thiomalate ligand of Myochrysine can inhibit platelet function.
McKague, Kathleen Mary Sophia, "The inhibitory action of myochrysine, a gold based, anti-rheumatic drug, on platelet activation" (1992). Open Access Dissertations and Theses. Paper 3723.