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Nitza Goldenberg-Cohen, Mark Vieyra, James D Nicholson, Dana Morzaev, Orkun Muhsinoglu, Shirel Weiss, David Zadok; Revatio (Sildenafil) protects retinal ganglion cells immediately after optic nerve crush injury, but high dose intraperitoneal may induce sporadic optic nerve stroke.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6223.
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© ARVO (1962-2015); The Authors (2016-present)
To measure the effect of Revatio on mouse ocular blood flow and RGCs survival with and without injury induction.
Seventy six mice were used. Right optic nerve crush (ONC) was induced in 36 mice, half of which (n=12 C57Bl6 and n=6 Thy-1-CFP) received intravitreal (IVT) injection of Revatio (0.24μg/3µl) immediately before injury and identical number of mice received no treatment. The left eyes served as a control. The remaining 40/76 mice were injected intraperitoneally (IP) (24μg/300µl), without ONC injury. FA was performed (day 0), retinal structure was examined histologically, RGCs were counted using H&E, and optic nerve using 2,3,5-Triphenyltetrazolium chloride (TTC) and luxol fast blue (LFB) staining for stroke detection (days 14, 21). . Quantitative real-time PCR was used to quantify gene expression of heme-oxegenase-1 (HO-1), superoxide dismutase-1 (SOD-1), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), Bcl-2 and BAX.
Maximal retinal vessels dilatation and increased choroidal effusion were detected by FA immediately after IVT Revatio, and 30 minutes after IP Revatio injection. At 21 days following ONC and IVT Revatio, RGCs were protected relative to ONC without treatment. CFP-Thy1 transgenic mice also showed protection with Revatio. Apoptotic gene expression in the retina had an anti-apoptotic profile, as compared with the untreated ONC. IVT without ONC produced no RGC loss or optic nerve stroke at 14 or 21 days after injection. However, following IP Revatio (n=40) 3 animals showed RGC loss by H&E and optic nerve damage by TTC or LFB staining. In the IVT group, gene expression analysis showed an increase in Bcl-2 on day 1 which reverted to baseline at day 3; no significant change was detected in the other gene levels. All genes measured in the IP group (relating to apoptotis, oxidative stress, and glial scar), increased (2-3 fold) on both days 1 and 3.
Revatio increased choroidal perfusion and mildly dilated retinal vessels. Following IP injection, possible association with optic nerve stroke (3/80 optic nerves) in correlation with an increased apoptosis and ischemic related gene expression. On the other hand, injection immediately before ischemic retinal damage induction, revealed a neuroprotective effect , probably associated with vessels dilatation and reperfusion.
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