Increased retinal toxicity of intravitreal tissue plasminogen activator in a central retinal vein occlusion model

Background Intravitreal injection of tissue plasminogen activator (tPA) is used to treat several ocular conditions, although excessive doses of intravitreal tPA cause retinal toxicity. Toxicity may increase in the ischemic retina, such as in central retinal vein occlusion (CRVO), because tPA toxicity to neural tissues increases under ischemic conditions. We investigated tPA toxicity to the retina in a CRVO rat model. Methods CRVO was induced in pigmented rats with rose Bengal-assisted laser photothrombosis. One hour after CRVO induction, 3 mu l of tPA (0.075, 0.75, 3, or 7.5 mu g) was injected intravitreally. Eyes that did not receive laser treatment, which served as non-CRVO controls, received tPA (0.75, 3, or 7.5 mu g). The same amount of balanced salt solution (BSS) was injected as a nondrug control. Eyes were enucleated at 12 hours after injection, and terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) staining was performed to evaluate retinal cell apoptosis. Results The number of TUNEL-positive cells increased in a dose-dependent manner in both non-CRVO and CRVO group and significantly (P = 0.002) increased when 0.75, 3, or 7.5 mu g of tPA was injected into the CRVO eyes. When comparing the number of TUNEL-positive cells between the eyes with and without CRVO that received the same treatment, apoptosis significantly increased in CRVO eyes. Conclusions Retinal toxicity associated with intravitreally injected tPA can increase in a dose-dependent manner and be exacerbated in CRVO eyes, suggesting that the dose of tPA should be reduced when tPA is used to treat eyes with CRVO.