Prophylactic Effects of Creatine and Metformin after Incomplete Retinal Ischemia

Abstract

Purpose : Retinal ischemia is implicated in many vision-threatening eye diseases, yet no effective treatment is available. Creatine serves a critical role in protecting tissue during ischemia. We hypothesize that prophylactic treatment with Creatine and Metformin will prevent impairments of retinal oxygen metrics and retinal layer thinning after bilateral common carotid artery occlusion (BCCAO).

Methods : Twenty rats were divided into 3 groups: sham, treatment (Tx), and vehicle. Rats in Tx and vehicle groups received intraperitoneal injections of Creatine + Metformin and saline, respectively. Daily administrations were initiated 7 days prior to and continued 7 days after BCCAO. Multimodal imaging was performed 7 days after BCCAO to measure retinal arterial and venous oxygen contents (O_2A, O_2V), total retinal blood flow (TRBF), and total retinal thickness (TRT). Arteriovenous oxygen content difference (O_2AV), oxygen delivery (DO₂), metabolism (MO₂), and extraction fraction (OEF) were calculated. Retinal sections were stained to measure retinal layer thickness. Linear mixed model analysis and ANOVA were used to compare metrics among groups.

Results : Compared to the sham group, TRBF, DO₂, and MO₂ were reduced, while O_2AV was increased in the vehicle group (P<0.02). In the Tx group, no differences were detected in O_2AV, DO₂, and TRBF compared to the sham group (P>0.2), whereas MO₂ was reduced (P= 0.002). Compared to the vehicle group, O_2AV was decreased in the Tx group (P=0.04), whereas no differences were detected in TRBF, DO₂, MO₂, OEF, O_2A, and O_2V (P>0.1). No differences were observed in O_2A, O_2V, and OEF among groups (P>0.08). Compared to the sham group, TRT and thickness of inner retina (IRL) and photoreceptor (PRL) layers were reduced in the vehicle group (P<0.02). In the Tx group, TRT and thickness of inner nuclear layer (INL) were not different compared to the sham group (P>0.4), whereas thickness of IRL and PRL were reduced (P<0.03). Compared to the vehicle group, thickness of retinal ganglion cell + nerve layers (RGC/NFL) was increased in the Tx group (P=0.04), whereas no differences were detected in IRL, inner plexiform layer (INL), and PRL (P>0.1). No differences were detected in outer plexiform and outer nuclear layers among groups (P>0.3).

Conclusions : Prophylactic treatment with Creatine and Metformin prevented elevations in O_2AV and increased RGC/NFL thickness after incomplete retinal ischemia.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.