Association of Quinone-Induced Platelet Anti-Aggregation with Cytotoxicity

Abstract

Various anti-platelet drugs, including quinones, are being investigated as potential treatments for cardiovascular disease because of their ability to prevent excessive platelet aggregation. In the present investigation 3 naphthoquinones (2,3-dimethoxy-1,4-naphthoquinone [DMNQ], menadione, and 1,4-naphthoquinone [4-NQ]) were compared for their abilities to inhibit platelet aggregation, deplete glutathione (GSH) and protein thiols, and cause cytotoxicity. Platelet-rich plasma, isolated from Sprague-Dawley rats, was used for all experiments. The relative potency of the 3 quinones to inhibit platelet aggregation, deplete intracellular GSH and protein thiols, and cause cytotoxicity was 1,4-NQ > menadione >> DMNQ. Experiments using 2 thiol-modifying agents, dithiothreitol (DTT) and 1-chloro-2,4-dintrobenzene (CDNB), confirmed the key roles for GSH in quinone-induced platelet anti-aggregation and for protein thiols in quinone-induced cytotoxicity. Furthermore, the anti-aggregative effects of a group of 12 additional quinone derivatives were positively correlated with their ability to cause platelet cytotoxicity. Quinones that had a weak anti-aggregative effect did not induce cytotoxicity (measured as LDH leakage), whereas quinones that had a potent anti-aggregative effect resulted in significant LDH leakage (84-96%). In one instance, however, p-chloranil demonstrated a potent anti-aggregative effect, but did not induce significant LDH leakage. This can be explained by the inability of p-chloranil to deplete protein thiols, even though intracellular GSH levels decreased rapidly. These results suggest that quinones that deplete GSH in platelets demonstrate a marked anti-aggregative effect. If this anti-aggregative effect is subsequently followed by depletion of protein thiols, cytotoxicity results.

Inhibition of the formation of advanced glycation end products by thymoquinone

“…Dietary quinones are commonly found in human foods, and are being extensively studied for their potentials against chronic degenerative diseases that affect humans (Takahashi et al, 2001). Quinones are clinically used as antitumor drugs, anti-allergic agents, components of multivitamins, and anti antiaggregative activities (Kim et al, 2001). Thymoquinone is a strong hydroxyl radical scavenger and a potent superoxide anion scavenger (Badary et al, 2003).…”

“…Similarly, AG at 10 mM, inhibited less than 10% of the thiol groups. Several quinones that deplete intracellular GSH and inhibit platelet aggregation may also be cytotoxic (Kim et al, 2001). However, thymoquinone at 20 lM depleted less than 5% of plasma protein thiols and showed no sign of toxicity by the lactate dehydrogenase results.…”

“…Glucose alone did not interfere with the measurement. Protein thiol levels were calculated on the basis of a glutathione calibration curve (Kim et al, 2001).…”

“…3. AGE products are characterized by strong fluorescence intensity at k exc = 370 nm and k em = 440 nm associated with fluorescent compounds, such as pentosidine (Cervantes-Laurean et al, 2006;Kiho et al, 2004;Kim et al, 2001). Fig.…”

Effect of Ketoprofen on Lactic Dehydrogenase from Human Platelets

“…Thrombocytopenia is also found to be associated with dexketoprofen, an active enantiomer of ketoprofen [21]. The platelet inhibition effects of ketoprofen can be exploited for conditions like myocardial infarction, stent thrombosis and for the drug development aspect for LdH inhibition in malaria as in the case of quinine and some azolebased compounds [22][23][24].…”