Abstract
Purpose: :
20-Hydroxyeicosatetraenoic Acid (20-HETE), an arachidonic acid metabolite, is a vasoconstrictor eicasanoid shown previously to induce both ischemia and oxidative stress in brain and coronary vasculature, both of which were reversed using an inhibitor of 20-HETE. The purpose of this study was to investigate if inhibition of 20-HETE could alleviate the functional and structural abnormalities observed in a rat model of oxygen-induced retinopathy.
Methods: :
Normal and oxygen-induced retinopathy (exposed to 80% oxygen) Sprague-Dawley (SD) juvenile rats were chronically injected intraperitoneally with either 2 mg/kg HET0016 (20-HETE inhibitor) or vehicle (DMSO) from P6-14. The effects of HET0016 on retinal function were evaluated via scotopic (intensity: -6.3 to 0.6 log cd.sec.m-2; 12 hours dark adaptation) and photopic (intensity: 0.9 log cd.sec.m-2; background: 30 cd.m-2) electroretinography (ERG) in both P30 and P60. The effect of HET0016 on retinal structure was evaluated using whole retina histology on both P30 and P60.
Results: :
Intraperitoneal injection of HET0016 to hyperoxic rats did not significantly affect the scotopic a- and b-wave amplitudes compared to hyperoxic rats injected with DMSO. However, both cohorts of hyperoxic rats had diminished scotopic and photopic b-wave amplitudes (averaging at 40% and 57% less for both) compared to control rats exposed to normal air at both P30 and P60. Photopic b-wave amplitudes of hyperoxic rats injected with HET0016 were higher at both P30 (17% higher) and P60 (15.5%) than in their hyperoxic cohorts injected with DMSO, though this was not significant enough. When comparing the ratio of scotopic b-wave amplitudes of HET0016 injected rats versus DMSO injected rats in both normoxic (0.81 and 0.90) and hyperoxic (1.00 and 1.06) cohort rats in both P30 and P60, a noticeable increase of 19% and 17% is seen in favor of HET0016 injected hyperoxic rats, respectively. A similar observation was noticeable with photopic b-wave amplitudes as well.
Conclusions: :
Our findings suggest that inhibition of 20-HETE may have some minor protective effects on retinal function in hyperoxic rats by attenuating the decrease in both the scotopic and photopic b-wave amplitudes. Whether these findings are due to the vasodilator and anti-oxidant properties of HET0016 on the ischemic phase of retinopathy or its anti-angiogenic effects on the neovascularization phase of retinopathy remain to be elucidated. It would be interesting to observe if inhibition of 20-HETE has any beneficial effects on other models of retinopathy, such as light-induced or diabetic retinopathy, andwhether this protective effects could be of greater impact if the drug was delivered topically or intravitreally.
Keywords: retina • electroretinography: non-clinical • retinopathy of prematurity