These findings suggest that nigral iron deposition, correlating with decreased serum ceruloplasmin levels, is a risk factor in Parkinson's disease across multiple motor phenotypic expressions.

Summary. Background: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a tumor vascular disrupting agent under clinical trials as an adjacent antitumor agent. DMXAA is structurally similar to flavone-8-acetic acid (FAA), an old tumor vascular disrupting agent with antiplatelet and antithrombotic effects. In contrast to FAA, which causes bleeding in tumor patients, no bleeding has been reported in patients receiving DMXAA. Whether DMXAA also affects platelet function is not clear. Objectives: To determine the effects of DMXAA on platelet function and explore the underlying mechanisms. Methods and Results: DMXAA concentration-dependently inhibited human platelet aggregation and ATP release induced by U46619, arachidonic acid, ADP, collagen, or ristocetin. Furthermore, DMXAA inhibited phosphorylation of Erk1/2 and Akt downstream of thromboxane A 2 signaling inhibition. DMXAA also inhibited human platelet phosphodiesterase. The antiplatelet effects were further confirmed using mice administered DMXAA intravenously. DMXAA dramatically inhibited thrombus formation in FeCl 3 -injured mouse mesenteric arterial thrombus model and laser-injured mouse cremaster arteriole thrombus model. Notably, at a dose exhibiting antithrombotic effects similar to those of clopidogrel in mice, DMXAA did not significantly increase bleeding. Conclusions: For the first time, we found that tumor vascular disrupting agent DMXAA has potent antiplatelet and antithrombotic effects without any bleeding diathesis. As DMXAA inhibits platelet activity with safe profile, DMXAA could be used as an efficacious and safe antiplatelet drug.

Summary. Background: Platelet ADP receptor P2Y 12 is well studied and recognized as a key player in platelet activation, hemostasis and thrombosis. However, the role of P2Y 12 in platelet apoptosis remains unknown. Objectives: To evaluate the role of the P2Y 12 receptor in platelet apoptosis. Methods: We used flow cytometry and Western blotting to assess apoptotic events in platelets treated with ABT-737 or ABT-263, and stored at 37°C, combined with P2Y 12 receptor antagonists or P2Y 12 -deficient mice. Results: P2Y 12 activation attenuated apoptosis induced by ABT-737 in human and mouse platelets in vitro, evidenced by reduced phosphatidylserine (PS) exposure, diminished depolarization of mitochondrial inner transmembrane potential (DYm) and decreased caspase-3 activation. Through increasing the phosphorylation level of Akt and Bad, and changing the interaction between different Bcl-2 family proteins, P2Y 12 activation inactivated Bak/Bax. This antiapoptotic effect could be abolished by P2Y 12 antagonism or PI3K inhibition. We also observed the antiapoptotic effect of P2Y 12 activation in platelets stored at 37°C. P2Y 12 activation improved the impaired activation responses of apoptotic platelets stressed by ABT-737. In platelets from mice dosed with ABT-263 in vivo, clopidogrel or deficiency of P2Y 12 receptor enhanced apoptosis along with increased Bak/Bax activation. Conclusions: This study demonstrates that P2Y 12 activation protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation, which may be physiologically important to counter the proapoptotic challenge. Our findings that P2Y 12 blockade exaggerates platelet apoptosis induced by ABT-263 (Navitoclax) also imply a novel drug interaction of antagonists.

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