Kamuvudine-9 protects retinal structure and function in a novel model of experimental rhegmatogenous retinal detachment

Abstract

Purpose : Before surgical repair of rhegmatogenous retinal detachment (RRD) is possible, irreversible inflammatory damage to the retina often occurs. An interim neuroprotective therapy could improve functional outcomes. Using a mouse model of RRD, we evaluate whether Kamuvudine-9 (K-9), a derivative of nucleoside reverse transcriptase inhibitors (NRTIs) that inhibits inflammasome activation, could protect the retina following RRD.

Methods : Persistent RRD was induced in C57BL/6J mice via subretinal injection (SRI) of carboxymethylcellulose (CMC). To simulate clinical practice, we also developed a model that achieves spontaneous retinal reattachment over 10 days (RRD/SRR). K-9 or PBS was administered via intraperitoneal injection during RRD. Inflammasome activation was monitored by caspase-1 cleavage (N=3), photoreceptor death was assessed by TUNEL staining (N=14), and cell death pathways were examined by caspase-8 cleavage and IL-18 ELISA (N=3). Retinal function was assessed by full-field scotopic electroretinography (1.0 log cd sec/m² stimulation, N=14). Two-tailed Student t-test was used for statistical analysis.

Results : RRD induced retinal inflammasome activation and photoreceptor death in mice, both of which were inhibited by K-9 (Fig. 1). K-9 also inhibited caspase-8 cleavage and IL-18 levels in the retina (Fig. 2, p<0.05). In the RRD/SRR model, K-9 protected retinal electrical function during RRD (Fig. 2).

Conclusions : K-9 exhibits both anti-inflammatory and neuroprotective activities in experimental RRD. Given its capacity to protect photoreceptors in RRD and enhance retinal function following reattachment, K-9 shows promise as a retinal neuroprotectant and warrants study in clinical RRD. Further, this novel RRD/SRR model may facilitate experimental evaluation of functional outcomes relevant to clinical RRD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

A) Caspase-1 at baseline and post-SRI. B) Day 3 caspase-1 after PBS, low-dose K-9 (K-9L), or high-dose K-9 (K-9H). C) Day 3 TUNEL(+) outer nuclear layer (ONL) cells after PBS, K-9L, or K-9H. In 1A-C, data is shown as mean ± SEM and *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.

 

A) IL-18 at baseline and day 3 after PBS or K-9L. B) Pro-caspase-8 and cleaved caspase-8 at baseline and day 3 following PBS or K-9L. C) Change in amplitude from baseline after PBS or K-9L. Days marked indicate significant differences between groups. In 2A-C, data is shown as mean ± SEM.