Neuroprotective Agents for Photoreceptor Rescue Following Experimental Retinal Detachment in Rodents: A Systematic Review

Purpose: The purpose of this study was to systematically evaluate neuroprotective interventions for photoreceptor preservation in rodent models of retinal detachment (RD). Methods: A systematic search of PubMed, Embase, Web of Science, and Google Scholar identified studies evaluating neuroprotective agents in rodent RD models. The primary outcome was a reduction in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells quantified on retinal tissue sections (histology-based); secondary outcomes included preservation of the outer nuclear layer (ONL) and electroretinography (ERG). Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. Results: Thirty-six studies (2007-2025) met inclusion criteria: 19 rat, 12 mouse, and 5 combined-species. Interventions included small molecules and recombinant proteins (n = 30), monoclonal antibodies (n = 3), peptides (n = 2), and extracellular vesicle therapy (n = 1). Eight (22.2%) evaluated US Food and Drug Administration (FDA)-approved agents for non-retinal indications. Anti-inflammatory interventions achieved the highest median TUNEL reduction (84.5%, interquartile range [IQR] = 62.3%-88.1%), followed by anti-inflammatory/antioxidant approaches (70.8%, IQR = 54.3%-76.0%), metabolic modulators (59.6%, IQR = 42.9%-64.8%), and anti-apoptotic agents (59.0%, IQR = 56.6%-69.3%). Between-group differences were not statistically significant (Kruskal-Wallis P = 0.32). Quantitative ERG data were available in only six studies (16.7%). The risk of bias was largely unclear across selection and performance domains, with assessor blinding most reported (63.9% low risk). Ten studies additionally evaluated genetically modified backgrounds as complementary mechanistic strata (n = 11 experiments). Conclusions: Inflammation-targeted therapies showed the most consistent numerical photoreceptor rescue across rodent RD studies. With eight studies evaluating FDA-approved agents, the field has clear repurposing opportunities; closing the translational gap will require rigorously designed, functionally oriented preclinical trials that reflect clinically realistic treatment delays.