Ophthalmology science · 2025
Topical WIN 55 212-2 Confers Long-Term Intraocular Pressure-Independent Neuroprotection in the DBA/2J Mouse Model of Glaucoma.
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Gallo Afflitto Gabriele, Chou Tsung-Han, Korsch Mascha Louisa, Aiello Francesco, Adornetto Annagrazia, Russo Rossella, Bagetta Giacinto, Nucci Carlo, Porciatti Vittorio
Аннотация
OBJECTIVE: To evaluate the neuroprotective efficacy of topical WIN 55 212-2 (WIN) in the DBA/2J mouse model of chronic glaucoma.
DESIGN: Preclinical 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 broken-stick generalized estimating equation 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, RNA-binding protein with multiple splicing (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 amplitudes as well as 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 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 downregulation and SBDP accumulation (SBDP-120 kDa: -65% at T10). Proteomics identified 15 downregulated proteins in WIN retinas associated with relief of lysosomal antiprotease and Ca2+-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.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
DESIGN: Preclinical 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 broken-stick generalized estimating equation 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, RNA-binding protein with multiple splicing (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 amplitudes as well as 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 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 downregulation and SBDP accumulation (SBDP-120 kDa: -65% at T10). Proteomics identified 15 downregulated proteins in WIN retinas associated with relief of lysosomal antiprotease and Ca2+-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.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.