SummaryBrain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays critical roles in the survival, growth, and maintenance of brain and peripheral neurons. We report the presence of BDNF protein in human platelets and its release upon agonist stimulation. The BDNF content of washed platelets varied widely, from 3.5 to 67 ng/ 4 X 108 platelets, averaging 25.2 ± 21.2 ng/4 X 108 platelets (mean ± SD). The BDNF concentration in platelet-poor plasma was low (1.7 ± 1.7 ng/ml, n = 11). Thrombin, collagen, the Ca++ ionophore A23187, and shear stress each induced a rapid release of BDNF from platelets. Up to only half of platelet BDNF was secreted upon agonist stimulation, suggesting that platelets may have a non-releasable pool of BDNF, or that the released BDNF binds to a recognition site on the platelet surface and is internalized, as occurs with serotonin. However, the cognate BDNF receptor, TrkB, was not detected in platelets. Nevertheless, the ability of BDNF to bind washed platelets was shown by FACS analysis confocal microscopy and by the binding and apparent internalization of [125I]-BDNF by platelets. A very high affinity site (Kd = 130 X 10−15 M, ∼80 sites/platelet) and a moderately high affinity site (Kd = 20 nM, ∼3750 sites/platelet) were identified. The BDNF content in two mega-karyocytic cell lines, DAMI and Meg-01, was only 0.1% of the content measured in platelets. No BDNF mRNA was detected by Northern blotting in these cell lines or in platelets. The pituitary gland was also ruled out as a source for platelet BDNF, since the BDNF content of rat platelets did not decrease 2 weeks after hypophysectomy. Thus, platelet BDNF is not acquired from the megakaryocyte or pituitary gland, but is probably acquired from other sources via the blood circulation. Platelets appear to bind, store and release BDNF upon activation at the site of traumatic injury to facilitate the repair of peripheral nerves or other tissues that contain TrkB.

Brain-derived neurotrophic factor (BDNF) is an abundant neurotrophin in brain and peripheral nerves, where it affects neural development, survival and repair after injury. BDNF has been detected in rat and human blood, but the source of circulating BDNF is not established. BDNF messenger and peptide were detected in cultured cells and in the culture medium of human umbilical vein endothelial cells. The expression of BDNF was up-regulated by elevation of intracellular cAMP and down-regulated by Ca 2+ ionophore, bovine brain extract and laminar fluid shear stress. These results suggest that vascular endothelial cells may contribute to circulating BDNF.z 2000 Federation of European Biochemical Societies.

Cilostazol (CLZ) was originally developed as a selective inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3). PDE3 inhibition in platelets and vascular smooth muscle cells (VSMC) was expected to provide an antiplatelet effect and vasodilation. Recent preclinical studies have demonstrated that CLZ also possesses the ability to inhibit adenosine uptake by various cells, a property that distinguishes CLZ from other PDE3 inhibitors, such as milrinone. After extensive preclinical and clinical studies, CLZ has been shown to have unique antithrombotic and vasodilatory properties based upon these novel mechanisms of action. CLZ was approved in 1988 for the treatment of symptoms related to peripheral arterial occlusive disease in Japan (Pletaal) and in 1999 in the U.S. and in 2001 in the U.K. (Pletal) for the treatment of intermittent claudication symptoms. Despite its remarkable antiplatelet properties, CLZ is not generally considered an antithrombotic agent in Western countries, perhaps due to the bulk of its antithrombotic preclinical and clinical development being conducted in Japan. In this review, the unique properties of CLZ are reviewed with the focus on CLZ as a unique antiplatelet agent targeting platelets and VSMC, demonstrating synergy with endogenous mediators and showing lowered risk of bleeding risk compared to other antiplatelet drugs.

As a powerful predictor of 5-year DSS among patients with NPC, the newly developed NPC-SVM classifier based on tumor-associated biomarkers will facilitate patient counseling and individualize management of patients with NPC.