Abstract
Purpose:
Hypoxia caused by ischemia plays a role in DR and is exacerbated during dark adaptation. Preclinical studies were undertaken to investigate the potential for emixustat HCl to reduce dark current and decrease photoreceptor oxygen (O2) consumption toward values observed in light adaptation.
Methods:
To test reduction in dark current, the Mn2+-enhanced magnetic resonance imaging (MEMRI) signal was used as a surrogate for retinal cGMP-gated cation channel current. Brown Norway rats (5/group) were given single doses of 1 or 10 mg/kg emixustat or vehicle by oral gavage, then 2 hours later, treated with tropicamide for pupil dilation and photobleached (5000 Lux white light for 10 minutes). Animals were then treated with Mn2+Cl and MEMRI measurements were obtained. To measure retinal PO2, urethane anesthetized Long Evans rats (3/group) were treated (emixustat 1 mg/kg IV) or left untreated, photobleached 30-60 minutes later (1000 Lux white light for 15 minutes), and then electroretinograms (ERGs) and retinal PO2 profiles were recorded with microelectrodes.
Results:
When dark current reduction was studied, vehicle-treated rats had increases in cation channel activity after photobleach consistent with those expected by dark adaptation. Emixustat-treated rats showed a dose-dependent reduction in cation channel activity, indicative of a reduction in dark current. This reduction was statistically significant compared to control (P = 0.002). When retinal PO2 was studied, ERGs recovered in the untreated rats but remained fully suppressed in emixustat-treated rats during the 2.5 hours after photobleaching, indicating a delay in dark adaptation. PO2 in the photoreceptor layers decreased toward the level observed in dark adaptation after photobleach, but remained elevated in emixustat-treated rats, consistent with the hypothesis that emixustat would delay dark adaptation and thereby reduce associated high photoreceptor oxygen consumption.
Conclusions:
Reduction of the dark current, as observed in emixustat-treated rats would be expected to reduce the metabolic activity of the photoreceptors in the outer retina. This reduction in metabolic activity was demonstrated independently by a prolonged elevation in retinal PO2 which, in turn, may prevent hypoxia in the retina and delay the progression of diabetic retinopathy.
Keywords: 499 diabetic retinopathy •
548 hypoxia •
648 photoreceptors