ET-1 led to a mean reduction in optic nerve blood flow of 68%. There were no significant differences in RGC survival among the four ET-1 doses used in this study. Pooled across all ET-1 doses, RGC survival decreased incrementally at 21, 42, and 84 days (P < 0.001; mean +/- SD, 0.77 +/- 0.25, 0.60 +/- 0.27, and 0.50 +/- 0.26, respectively) and was statistically significantly lower at each time point than in the BSS-treated animals. The axon survival data also showed a similar time-dependent loss. Only one of 21 animals showed significantly increased disc cupping, and there was no relationship between RGC survival and change in cupping. CONCLUSIONS. Chronic administration of ET-1 to the rat optic nerve results in a time-dependent loss of RGCs and their axons without apparent change in optic disc topography.
Patients with glaucoma have an abnormal increase in plasma ET-1 after the body cools. It is possible that at least in some patients, increased levels of ET-1 in response to vasospastic stimuli may be involved in the pathogenesis of glaucomatous damage.
Tumor cells use activated platelets to promote their proliferation and metastatic potential. Because platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets, we investigated the potential of the reversible P2Y12 inhibitor ticagrelor, a clinical agent used in the prevention of cardiovascular and cerebrovascular events, to inhibit tumor adhesion and metastasis. In B16-F10 melanoma intravenous and intrasplenic metastasis models, mice treated with a clinical dose of ticagrelor (10 mg/kg) exhibited marked reductions in lung (84%) and liver (86%) metastases. Furthermore, ticagrelor treatment improved survival compared to saline-treated animals. A similar effect was observed in a 4T1 breast cancer model, with reductions in lung (55%) and bone marrow (87%) metastases following ticagrelor treatment. In vitro, B16-F10 cells exhibited decreased interaction with platelets from ticagrelor-treated mice compared to saline-treated mice, an effect similar to that observed with blockade of glycoprotein IIbIIIa. Similarly, B16-F10 cells co-incubated with platelets from ticagrelor-treated mice exhibited reduced adhesion to endothelial monolayers compared to those co-incubated with platelets from saline-treated animals, an effect also observed in vivo. Interestingly, pretreatment of endothelial monolayers with ticagrelor did not result in reduced tumor cell adhesion. These findings support a role for P2Y12-mediated platelet activation in promoting metastases, and provide proof-of-concept for the clinical use of ticagrelor in the prevention of tumor metastasis.It is now well established that normal platelet function is required for cancer progression.1 Mice with pharmacologically or genetically induced thrombocytopenia have dramatically fewer metastases, an effect reversed by transfusing platelet-rich plasma (PRP).2,3 Cancer cells that more effectively activate platelets have been shown to produce more metastases.4 Activated platelets are thought to promote metastasis by shielding tumor cells from natural killer cells, 4,5 enhancing adhesion to and transmigration across endothelium 6,7 and promoting angiogenesis and proliferation through release of small molecules such as ATP and ADP. 6,8,9 The clinical observation that aspirin use leads to reduced metastasis risk further supports a role for platelets in promoting tumor spread. 10 Schumacher et al. 6 demonstrated that ATP released by platelets interacts with purinergic P2Y2 receptors on endothelial cells, rendering them more susceptible to tumor cell extravasation; P2Y2-deficient mice, in turn, exhibited decreased tumor metastasis. As platelet activation is largely mediated through ADP engagement of the purinergic receptor P2Y12 on platelets, P2Y12 represents an attractive target for inhibiting tumor metastasis. Recently, Wang et al. demonstrated that tumor metastases are reduced in P2Y12-deficient mice.11 In our report, we investigated the potential of a clinical agent, the reversible and specific P2Y12 inhibitor ticagrelor, to inhib...
The grading scheme had good inter- and intraobserver agreement, and high correlation with the TEM methods. It is a practical and time-saving method, requiring less than 1 minute per nerve and is an alternative to sampling methods that can yield significant errors.
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