Efavirenz, a CYP46a1 activator Ameliorates Pathological Neovascularization in A Mouse Model of Oxygen-Induced Retinopathy

Suwanee, GA

Introduction: In a prior study, we documented the predominant reliance of the developing retina on the alternate bile acid (BA) synthesis pathway. However, in the context of oxygen-induced retinopathy (OIR) in mouse models, retinal BA synthesis undergoes significant dysregulation, marked by a pronounced reduction in the activity of the key rate-limiting enzyme, Cytochrome P450 enzymes (CYP or P450) 46A1.

Objective: The objective of this current investigation is to assess the impact of efavirenz (EFV)-mediated activation of CYP46A1 on retinal neovascularization in OIR mice, a model representative of retinopathy of prematurity (ROP).

Methods: Seven-day-old (P7) C57BL/6J mice were subjected to the OIR procedure following the methodology outlined by Smith et al. OIR-induced mice received EFV treatment at doses of either 10 or 20 mg/kg body weight from P7 to P17, while age-matched room air mice were included as controls. Retinal neovascularization and avascular area were evaluated in mouse retinal flat mounts stained with isolectin-B4.

Results: Our findings revealed that while a dosage of 10 mg/kg EFV did not confer significant protection against OIR pathology, treatment with 20 mg/kg EFV led to a notable reduction in both avascular area and pathological neovascularization within OIR mouse retinas. Importantly, we observed no substantial evidence of retinal or systemic toxicity associated with EFV treatment in neonatal mice.

Conclusion: In summary, our preliminary investigations suggest that pharmacological activation of CYP46A1 using efavirenz holds promise in ameliorating critical pathological features linked to neovascularization in OIR mice, thereby potentially positioning efavirenz as a therapeutic candidate for ROP.