Protective effects of D-glucaro-1,4-lactone against oxidative modifications in blood platelets

Peroxynitrite (ONOO-), a highly reactive species, modulates platelet activation and function. Modifications of platelet proteins induced by ONOO- may be an important factor in the pathogenesis of platelet-related diseases. The defence mechanisms against ONOO- are therefore crucial for normal cellular function. Recently, there has been an increased interest in the screening of natural products present in the diet and herbals for possible antioxidative agents (ONOO( scavengers). D-glucaro-1,4-lactone (1,4-GL), formed from D-glucaric acid (GA), a natural compound found in fruits and vegetables, possesses detoxifying and anticancerogenic properties. However, the effect of this compound on platelet activation is unknown.

We investigated the effects of 1,4-GL on nitrative and oxidative alteration of platelet proteins and lipid peroxidation caused by two strong oxidants: ONOO- and hydroperoxide (H2O2). The action of 1,4-GL on platelet aggregation induced by adenosine diphosphate (ADP) was also studied. Exposure of platelets to ONOO- or H2O2 resulted in an increase in the level of carbonyl groups (approximately three-fold and two-fold, respectively). In the presence of 1,4-GL, a significant decrease (about 50% for the highest concentration of 1,4-GL) in carbonyl group formation was observed; however the level of nitrotyrosine residues in platelets treated with ONOO- remained unchanged.

We demonstrated an inhibitory effect of 1,4-GL on lipid peroxidation in platelets treated with ONOO- (0.1mM) or H2O2 (2mM). 1,4-GL inhibited platelet lipid peroxidation by about 40%. In the presence of 1,4-GL, peroxidation of plasma lipids was also reduced by about 40%. These results demonstrate that 1,4-GL possesses antioxidative properties and reduces the activation of blood platelets.