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Srilakshmi M. Sharma, Wen-Ying Wu-chen, Zhiyong Yang, Fernandino L. Vilson, Yan Guo, Neil R. Miller, Donald J. Zack, Steven L. Bernstein; Sunitinib Malate Preserves Retinal Ganglion Cells in Rodent NAION. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6614.
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© ARVO (1962-2015); The Authors (2016-present)
Sunitinib malate (Sutent) is a tyrosine kinase inhibitor used in cancer chemotherapy. Recent data suggest that it can protect retinal ganglion cells (RGCs) from a variety of insults. We wanted to determine whether sunitinib could protect RGCs from the axonal ischemic insult associated with the rodent model of anterior ischemic optic neuropathy (rAION).
rAION was induced using a 532 nm frequency doubled YAG laser to activate intravenously administered rose Bengal in optic nerve capillaries. Following induction, sunitinib (10mg/kg), or PBS were injected intraperitoneally every two days for up to 21 days. Apoptotic RGCs were identified by intravitreal injection of FITC-labeled Annexin V, at days 6, 10, 14 and 18. Annexin (+) cells were colocalized to RGC nuclei by DAPI and BRN3a immunohistochemistry using confocal microscopy. At 30 days post-induction, remaining animals were euthanized, and RGC stereology was performed on Brn3a immunostained whole mount retinae. Transmission electron microscopy (TEM) was performed on optic nerve sections.
RGC survival increased in animals treated with sunitinib (58.3 +/- 7.1% p=0.044) vs vehicle-treated (37.3 +/- 6.4%) compared with naive retina. TEM showed increased numbers of RGC axons in optic nerves of sunitinib-treated rAION. RGC-apoptotic cell numbers were reduced in rAION-affected retinal areas in sunitinib-treated animals at day 18 (p=0.002), with a trend towards reduced apoptosis at day 10 (p=0.06).
This pilot study suggests that sunitinib can promote RGC survival in rAION. Sunitinib's neuroprotective activity in this model is associated with inhibition of RGC apoptosis. If confirmed with larger ongoing studies, this and other studies (Yang et al, unpublished observations) indicate that protein kinase inhibition may provide a novel therapeutic approach for optic neuropathies, including NAION.
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