Abstract 285: Short- and Long-term Treatment of Pyridoxamine, an Inhibitor of Advanced Glycation End Products, Attenuates Platelet-neutrophil Interactions and Vascular Occlusion in Sickle Cell Disease

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Sickle cell disease (SCD) is an inherited blood disorder, leading to sickling and hemolysis of red blood cells, activation of intravascular cells, and chronic inflammation. Recurrent vaso-occlusion (VOC) is the hallmark of SCD and results from intravascular cell-cell interactions. VOC is a crucial trigger for severe pain crisis, the common complication in SCD patients. Pyridoxamine (PHD-14, PCT/US2015/016753) inhibits the formation of advanced glycation end products (AGEs) that enhance reactive oxygen species (ROS). Since the plasma AGE levels are associated with hemolysis-related complications in SCD, we hypothesized that pyridoxamine has beneficial effects on the microvascular environment and prevents organ damage in SCD. Using intravital microscopy, we found that a single oral administration of pyridoxamine (10-100 μg/g body weight) dose-dependently reduced intravascular cell-cell interactions and increased blood flow rates in cremaster vessels of Berkeley mice challenged with TNF-α or hypoxia/reoxygenation, resulting in improved survival. Compared with single therapy, co-administration of hydroxyurea (HU), a main therapy for SCD, and pyridoxamine exhibited a greater inhibitory effect on intravascular cell-cell interactions. Long-term treatment of pyridoxamine-containing water (2 g/L for 3 months) significantly reduced the plasma level of AGEs and intravascular cell-cell interactions as observed in the single oral administration. Importantly, pyridoxamine treatment attenuates tissue damage in the lungs and liver. Mechanistically, treatment of mouse and human platelets with pyridoxamine significantly inhibited aggregation, αIIbβ3 activation, granule secretion and ROS generation following agonist stimulation, indicating the inhibitory effect on the signaling pathway of platelet activation. In neutrophils, pyridoxamine treatment reduced ROS production without affecting integrin activation after fMLP stimulation. Our results provide strong evidence that pyridoxamine alone or in combination with HU has the potential to be developed for the treatment of acute VOC-mediated complications in SCD patients and warrant further study of pyridoxamine in a clinical trial to treat acute vaso-occlusive crises in SCD.

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