ABSTRACT
BACKGROUND AND PURPOSE: Oncocalyxone A (OncoA) has a concentration-dependent anti-platelet activity. The present study aimed to further understand the mechanisms related to this effect. EXPERIMENTAL APPROACH: Human platelet aggregation was measured by means of a turbidimetric method. OncoA (32-256 microM) was tested against several platelet-aggregating agents, such as adenosine diphosphate (ADP), collagen, arachidonic acid (AA), ristocetin and thrombin. KEY RESULTS: OncoA completely inhibited platelet aggregation with a calculated mean inhibitory concentration (IC50-microM) of 122 for ADP, 161 for collagen, 159 for AA, 169 for ristocetin and 85 for thrombin. The anti-aggregatory activity of OncoA was not inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). OncoA, at a concentration that caused no significant anti-aggregatory activity, potentiated sodium nitroprusside (SNP) anti-aggregatory activity (18.8+/-2.9%-SNP vs 85.0+/-8.2%-SNP+OncoA). The levels of nitric oxide (NO) or cAMP were not altered by OncoA while cGMP levels were increased more than 10-fold by OncoA in resting or ADP-activated platelets. Flow cytometry revealed that OncoA does not interact with receptors for fibrinogen, collagen or P-selectin. Nevertheless, OncoA decreased the binding of antibodies to GP Ibalpha, a glycoprotein that is related both to von Willebrand factor and to thrombin-induced platelet aggregation. CONCLUSION AND IMPLICATIONS: OncoA showed anti-aggregatory activity in platelets that was associated with increased cGMP levels, not dependent on NO and with blocking GP Ibalpha glycoprotein. This new mechanism has the prospect of leading to new anti-thrombotic drugs.
Subject(s)
Anthraquinones/pharmacology , Cyclic AMP/biosynthesis , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIb-IX Complex/metabolism , Adenosine Diphosphate/pharmacology , Adenosine Triphosphate/metabolism , Adolescent , Adult , Anthraquinones/isolation & purification , Anthraquinones/metabolism , Blood Platelets/drug effects , Blood Platelets/metabolism , Cyclic AMP/blood , Cyclic GMP/blood , Cyclic Nucleotide Phosphodiesterases, Type 5/blood , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Female , Flow Cytometry , Guanylate Cyclase/blood , Guanylate Cyclase/metabolism , Humans , In Vitro Techniques , Male , Middle Aged , Nitric Oxide/metabolism , Platelet Aggregation Inhibitors/metabolism , Protein Binding , Thromboxane A2/physiologyABSTRACT
Moyamoya disease in childhood is frequently accompanied by manifestations of ischemia; cerebral hemorrhage is unusual in patients younger than 15 years of age. Previous studies suggest an association of childhood moyamoya disease, which is often bilateral, with Down syndrome. Possible etiologic factors of moyamoya disease in Down syndrome are discussed.
