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David A Antonetti, Chengmao Lin, Timothy S Kern, Steven F Abcouwer; Trapping all trans retinal is protective to vascular damage in ischemia reperfusion. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3582.
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© ARVO (1962-2015); The Authors (2016-present)
Previous research suggests that photoreceptor (PR) damage contributes to changes in inner retinal vascular function in diabetic retinopathy. Treatment with retinylamine can improve retinal vascular function in mouse models of diabetes but the mechanism is unknown. All trans retinal (atRAL) is a toxic aldehyde that may be released from damaged PR. We hypothesized that atRAL released from damaged photoreceptors contributes to retinal vascular permeability and trapping atRAL or decreasing atRAL production would decrease the vascular permeability response.
We employed a mouse ischemia reperfusion (IR) model that induces a rapid and robust increase in inner retinal vascular permeability. IR injury was unilaterally produced by injection of saline into the anterior chamber to elevate intraocular pressure to 75-100 mmHg and restrict retinal and choroidal blood flow for 90 min, followed by natural reperfusion. Contralateral Sham-treated eyes received a needle puncture only. Vascular permeability was assayed 4 h or 48 h later by measuring the retinal accumulation of circulating FITC-BSA. Mice were treated by intraperitoneal injection of drugs 24 h before IR. The drugs tested include: emixustat, a retinylamine derivative that inhibits RPE65 retinoid isomerase activity and contains a primary amine group that forms a Shift base conjugate with atRAL; MB-002, a diol derivative of emixustat that inhibits RPE65 activity but lacks a primary amine group; and amlodipine besylate, a separate primary amine-containing compound that does not inhibit RPE65.
Treatment of mice with emixustat significantly attenuated the IR induced permeability by ~50% at 48 h after reperfusion but not at 4 h after reperfusion, consistent with the longer time to outer retina damage and atRAL release. MB-002 lacked this protective effect, while amlodipine besylate attenuated IR induced vascular permeability. Strikingly, dark-adapting mice for 24 h to decrease atRAL content in PR likewise diminished IR induced permeability by ~50% at 48 h after reperfusion.
Trapping or decreasing atRAL can attenuate vascular permeability in the inner retina after IR damage. These studies suggest that atRAL release can contribute to vascular dysfunction and trapping atRAL may provide a rationale strategy to treat inner retinal vascular dysfunction where outer retinal damage contributes to the disease process.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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