Parthenolide and the derivative of 4- methylideneisoxazolidin-2-one inhibit aggregation of human blood platelets

Parthenolide (Ptn), a member of sesquiterpene lactones, isolated from a herb — feverfew (Thanaceum parthenium), has been recently examined as anti-cancer and anti-inflammatory agent. It was also studied in prophylaxis and treatment of the migraine in humans. Some incidental reports suggested also its anti-platelet activity. In this study, we investigated the effect of Ptn and the synthesized 1-tert-butoxycarbonyl-5-isopropyl-4-methylideneisoxazolidin-2-one (AJ86) on platelet aggregation. Blood was obtained from 10 healthy volunteers, 7 women and 3 men, aged 22÷43 years. Two variants of platelet aggregometry were applied: electrical (impedance) aggregation in whole blood and turbidimetric [optical] aggregation in platelet rich plasma (PRP). Whole blood or PRP were preincubated with Ptn (25÷750 μM) or AJ86 (25÷750 μM) for 30 min at 37oC. Platelet aggregation was triggered with ADP (5 mM) and recorded for 10 minutes. We found that both Ptn and AJ86 strongly inhibited ADPinduced platelet aggregation. Regarding the studies on aggregation in PRP, IC50 for Ptn amounted to 75.2 μM, whereas the inhibitory potency of AJ86 was even stronger (IC50=50.1 μM). In whole blood, the effectiveness of either Ptn or AJ86 as anti-aggregation agent was about 5-fold lower, compared to the aggregation in PRP; IC50 values were 350 μM and 250 μM, respectively. In the light of the obtained results we conclude that: i) both Ptn and AJ86 — a newly synthesized methylideneisoxazolidinone derivative — are strong inhibitors of platelet aggregation, effective at micromolar concentrations; ii) the inhibitory effect of AJ86 is even stronger that Ptn; iii) the inhibition potency of both Ptn and AJ86 is remarkably stronger in PRP than in whole blood. We believe, that α-methylidenelactone moiety, which is a common structural motif shared by both Ptn and AJ86, may be responsible for their anti-platelet activity. Acknowledgements: This study was supported Medical University of Lodz funds 50216-652. P14.2