Abstract
Purpose :
We previously reported that the developing retina relies primarily on the alternate bile acid (BA) synthesis pathway. However, in the oxygen-induced retinopathy (OIR) mouse model, retinal BA synthesis is significantly dysregulated and is characterized by a significant loss of rate-limiting BA generating enzymes Cytochrome P450 enzymes (CYP or P450) 46A1 and 27A1. The present study aims to evaluate the effects of efavirenz (EFV)-mediated CYP46A1 activation on retinal neovascularization in an oxygen induced retinopathy (OIR) mouse model of retinopathy of prematurity (ROP).
Methods :
Seven days old (P7) C57BL/6J mice were subjected to the OIR procedure according to the protocol of Smith et al. Mice undergoing OIR were treated with either 10 or 20 mg/kg body weight of EFV from P7 to P17, with age-matched room air mice serving as the control. Retinal neovascularization and avascular area were studied in mouse retinal flat mounts stained with isolectin-B4. Additionally, retinal cryosections were immunostained with specific markers to study reactive gliosis, microglia activation, and loss of retinal ganglion cells.
Results :
Our results indicated that while 10 mg/kg EFV did not provide significant protection against OIR pathology, 20 mg/kg EFV treatment significantly reduced avascular area and pathological neovascularization in OIR mice retinas. Further, 20 mg/kg EFV treatment significantly reduced retinal reactive gliosis and microglia activation and improved retinal ganglion cell survival in OIR mice retinas. Importantly, we did not observe significant retinal or systemic toxicity with EFV treatment in neonatal mice.
Conclusions :
In summary, our preliminary studies indicate that pharmacological CYP46A1 activation using efavirenz could ameliorate key pathological features associated with pathological neovascularization in OIR mice, thus potentially implicating efavirenz as a therapy for ROP.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.