Abstract
Purpose :
Proliferative retinopathies are the leading cause of irreversible blindness in all ages, and there is a critical need to identify novel therapies. The present study investigated the impact of Triciribine (TCBN), a tricyclic nucleoside analog and a weak Akt inhibitor, in retinal neurovascular injury, vascular permeability, and inflammation in oxygen-induced retinopathy (OIR).
Methods :
C57BL/6 mouse pups at post-natal day 7 (P7) were subjected to OIR followed by injections (i.p.) of TCBN (1 mg/kg) or vehicle (saline) during P14-P16. Age-matched mice maintained at normoxia, and treated with vehicle or TCBN served as the controls. Retinal flatmounts and sections (P17) were processed for immunostaining, and fresh frozen retinas used for Western blotting or qRT-PCR studies. Fluorescein angiography (FA) and spectral domain optical coherence tomography (SD-OCT) was performed at the P21 and P30, respectively. NIH ImageJ was utilized for quantification. Statistical analyses performed using GraphPad Prism 9.
Results :
TCBN treatment significantly reduced retinal pathological neovascularization and vaso-obliteration (N = 10-12, P < 0.05), accompanied by reduced cytokine (TNF-α, IL-6, and MCP-1) mRNAs (N = 5-8, P < 0.05) and decreased expression of iba1 and F4/80 (macrophagic/microglia cell markers) (N = 5, P < 0.05) compared to vehicle-treated OIR mice. Interestingly, OIR upregulated the expression of tight junction protein CLDN5 (a key mediator of blood-retinal barrier integrity), which was restored by TCBN treatment (N = 5, P < 0.01). In particular, TCBN-treated OIR mice displayed significantly reduced vascular leakage compared with vehicle-treated OIR mice, as analyzed by FA analysis (N = 6-14, P < 0.01) and extravasated albumin measurement (N = 6, P < 0.01). Of note, there were no changes in the retinal architecture in response to TCBN in the OIR mice (N = 5-8, P > 0.05). TCBN treatment did not affect the retinal architecture in the normoxia mice compared with control mice (N = 5-8, P > 0.05).
Conclusions :
TCBN protects against neovascularization, restores blood-retinal barrier homeostasis, and reduces retinal inflammation without adverse effects on the retinal structure in a mouse model of OIR. Taken together, our data suggest that TCBN may provide a novel therapeutic option for proliferative retinopathy.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.