Abstract
Abstract: :
Purpose: Retinal microvascular cells in early diabetes are thought to be in a pro–apoptotic state. This preliminary study is to investigate whether utilization of caspase inhibitors, the final apoptotic pathway blockers, can delay the injury of blood–retinal barrier (BRB). Methods: Male Sprague–Dawley rats were treated with streptozotocin (60 mg/kg). Diabetic animals were randomly divided for Caspase–inhibitor (CAI) treatment and observation groups. Both groups were treated with 6 units insulin zinc suspension injected subcutaneously three times a week to maintain body weight and improve long–term survival. For CAI groups, the treatment started as early as 1–day diabetic history. Intravitreal injection of CAIs, Z–DEVD–FMK (a caspase 3 inhibitor) or pan caspase inhibtor Z–VAD–FMK, was performed once a week to target the vitreal level of 10 µmol/l. At 1–week, 4–week, 12–week and 16–week intervals, BRB breakdown was determined by injecting Evans blue into the circulation and then calculating extravasated Evans blue into the retinal tissue. The BRB breakdown was expressed as µl plasma / (g retinal dry weight) x hour. After the BRB study, the animals were sacrificed and the microaneurysms (MAs) in flat mounted retinas were quantified. Results: Significant BRB breakdown of untreated diabetic rats was noted at the 4–week interval of diabetic induction in comparison with the normal rats (p<0.01). In the CAI treatment group, BRB was essentially unchanged at 4–week interval. In comparison with untreated diabetic retinas the leakage of the retina treated with CAIs was reduced 67+10% and 43+8% at 12 and 16–week intervals, respectively. The less injured BRB was correlated with less MAs. Conclusions: Caspase inhibitor treatment maintains the integrity of BRB in diabetic retinas. This finding indicates apoptotic process can be delayed by CAI in early diabetic retina, which opens a new therapeutic avenue for early diabetic retinopathy.
Keywords: diabetic retinopathy • apoptosis/cell death • drug toxicity/drug effects