The sulphydryl oxidizing reagent diamide affects phosphoinositide-mediated signal transduction: implications for the pathogenesis of Alzheimer's disease.
In fura-2-labelled human platelets, the thiol oxidising agent diamide decreases the intracellular calcium response to thrombin and serotonin without affecting the basal calcium levels. The effect of diamide on the thrombin response could be prevented by pre-treatment with dithiothreitol (DTT) and reduced when DTT was added 60 s after diamide. The effects of diamide and hydrogen peroxide on the thrombin response were additive. Hydrogen peroxide also produced a calcium response per se, but this response was not affected by diamide. Hydrogen peroxide increased rat brain phosphoinositide hydrolysis and reduced the response to carbachol and noradrenaline, whereas diamide was without effect. The binding of [3H]inositol-1,4,5-trisphosphate to human platelet membranes was inhibited by diamide but not by hydrogen peroxide. Thus diamide affects the phosphoinositide signal transduction pathway in a qualitatively different manner from that found with hydrogen peroxide. It is suggested that oxidative stress may contribute to the disturbances in the phosphoinositide transduction pathway that are found in Alzheimer's disease.
Fowler
C J
CJ
Department of Pharmacology, Umeå University, Sweden. cf@pharm.umu.se
Tiger
G
G
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D003958:Diamide; D004229:Dithiothreitol / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006868:Hydrolysis; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D016877:Oxidants; D018384:Oxidative Stress / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D012701:Serotonin / Q000494:pharmacology; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*
D016877:Oxidants; D010716:Phosphatidylinositols; D013439:Sulfhydryl Reagents; D003958:Diamide; D012701:Serotonin; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D006861:Hydrogen Peroxide; D013917:Thrombin; D004229:Dithiothreitol; D009638:Norepinephrine