{"doi":"10.1016/j.xops.2025.100918","title":"Topical WIN 55 212-2 Confers Long-Term Intraocular Pressure–Independent Neuroprotection in the DBA/2J Mouse Model of Glaucoma","abstract":"Objective To evaluate the neuroprotective efficacy of topical WIN 55,212-2 (WIN) in the DBA/2J mouse model of chronic glaucoma. Design Pre-clinical controlled study. Subjects Ninety 6-month-old DBA/2J mice (180 eyes) grouped in Untreated (UN), WIN 1%, or WIN 1% + rimonabant (RIM). Methods In vivo recordings were performed at 6 (T6), 8 (T8) and 10 (T10) months. Two brocken-stick generalized estimating-equation (GEE) models were fitted: Model 1 treated Intraocular Pressure (IOP) as a covariate; Model 2 treated IOP as an explicit predictor. Retinal lysates underwent Western blotting (LC3-II, p62, Parkin, Optineurin, RBPMS, α-spectrin breakdown products [SBDPs]) and untargeted proteomics for exploratory mechanistic granularity assessment. Main Outcome Measures pattern electroretinogram (PERG), IOP, flash-ERG (FERG) and photopic negative response (PhNR) amplitudes; ganglion-cell-complex (GCC) thickness. Results At T8, IOP was 11.5 ± 1.4 mmHg in WIN compared to 22.0 ± 2.0 mmHg in UN and 21.7 ± 2.3 mmHg in RIM (p < 0.001). Similar results were observed at T10 (WIN: 19.4 ± 3.0 mmHg; UN: 23.4 ± 2.0 mmHg; RIM: 22.7 ± 3.2 mmHg) (p < 0.001). Statistically significant differences in PERG amplitude were observed among groups at both T8 and T10. In Model 1, WIN-treated eyes demonstrated a 6.1 μV higher PERG amplitude at T10 (p < 0.001). Model 2 showed no significant WIN×IOP×T10 interaction (p = 0.757), suggesting that WIN-mediated protection is largely independent of IOP. Time-dependent decline in FERG was similar among groups. Photopic Negative Response (PhNR) amplitudes and GCC thickness decreased in all groups, with significant intergroup differences favoring WIN at both T8 and T10 (both p < 0.001). Molecularly, WIN reduced LC3-II by 35% at T10 without p62 accumulation, doubled Parkin and lowered Optineurin at T8, and markedly blunted RBPMS down-regulation and SBDP accumulation (SBDP-120 kDa: –65% at T10). Proteomics identified 15 down-regulated proteins in WIN retinas associated with relief of lysosomal-antiprotease and Ca 2+ -stress pathways and enhanced autophagy–mitophagy flux. Conclusions Topical WIN 1% transiently lowers IOP, preserves retinal ganglion-cell function, and attenuates structural and molecular degeneration in a seemingly cannabinoid receptor 1-dependent and IOP-independent fashion, thus representing a promising neuroprotective strategy for glaucoma.","journal":"Ophthalmology Science","year":2025,"id":536548,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9005,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":496208,"name":"Tsung‐Han Chou","orcid":"0000-0001-6154-6283","position":1,"is_corresponding":false},{"id":1421881,"name":"Mascha Louisa Korsch","orcid":null,"position":2,"is_corresponding":false},{"id":1421370,"name":"Francesco Aiello","orcid":"0000-0001-6479-1807","position":3,"is_corresponding":false},{"id":1421371,"name":"Annagrazia Adornetto","orcid":"0000-0003-1869-2642","position":4,"is_corresponding":false},{"id":1043971,"name":"Rossella Russo","orcid":"0000-0001-8758-6523","position":5,"is_corresponding":false},{"id":1421372,"name":"Giacinto Bagetta","orcid":"0000-0001-8540-6218","position":6,"is_corresponding":false},{"id":1421882,"name":"Carlo Nucci","orcid":null,"position":7,"is_corresponding":false},{"id":320100,"name":"Vittorio Porciatti","orcid":"0000-0002-1592-3532","position":8,"is_corresponding":false},{"id":1087618,"name":"Gabriele Gallo Afflitto","orcid":"0000-0003-0013-6189","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T02:52:05.227140Z","pmid":"41140902","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}