Significance: Retinal degenerative diseases affect specific regions of the retinal pigment epithelium (RPE), suggesting the presence of functionally different RPE subpopulations. To identify these subpopulations in human eyes, we generated the first complete morphometric map of the RPE at single-cell resolution using artificial intelligence–based software. We identified five concentric RPE subpopulations, including a ring of RPE cells with cell area similar to macula in the periphery of the eye. Moreover, we found that specific RPE subpopulations are differentially susceptible to monogenic and polygenic retinal diseases. The results obtained here will allow study of molecular and functional RPE differences responsible for regional retinal diseases and will help develop precise cell and gene therapies for specific degenerative eye diseases.

To determine whether the functional effects of oral supplementation with Saffron, a natural compound that proved to be neuroprotective in early age-related macular degeneration, are influenced by complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk genotypes.

Crocus sativus L. belongs to the Iridaceae family and it is commonly known as saffron. The different cultures together with the geoclimatic characteristics of the territory determine a different chemical composition that characterizes the final product. This is why a complete knowledge of this product is fundamental, from which more than 150 chemical compounds have been extracted from, but only about one third of them have been identified. The chemical composition of saffron has been studied in relation to its efficacy in coping with neurodegenerative retinal diseases. Accordingly, experimental results provide evidence of a strict correlation between chemical composition and neuroprotective capacity. We found that saffron’s ability to cope with retinal neurodegeneration is related to: (1) the presence of specific crocins and (2) the contribution of other saffron components. We summarize previous evidence and provide original data showing that results obtained both “in vivo” and “in vitro” lead to the same conclusion.

Experimental studies demonstrated that saffron (Crocus sativus) given as a dietary supplement counteracts the effects of bright continuous light (BCL) exposure in the albino rat retina, preserving both morphology and function and probably acting as a regulator of programmed cell death [1]. The purpose of this study was to ascertain whether the neuroprotective effect of saffron on rat retina exposed to BCL is associated with a modulation of the endocannabinoid system (ECS). To this aim, we used eight experimental groups of Sprague-Dawley rats, of which six were exposed to BCL for 24 hours. Following retinal function evaluation, retinas were quickly removed for biochemical and morphological analyses. Rats were either saffron-prefed or intravitreally injected with selective type-1 (CB₁) or type-2 (CB₂) cannabinoid receptor antagonists before BCL. Prefeeding and intravitreally injections were combined in two experimental groups before BCL. BCL exposure led to enhanced gene and protein expression of retinal CB₁ and CB₂ without affecting the other ECS elements. This effect of BCL on CB₁ and CB₂ was reversed by saffron treatment. Selective CB₁ and CB₂ antagonists reduced photoreceptor death, preserved morphology and visual function of retina, and mitigated the outer nuclear layer (ONL) damage due to BCL. Of interest, CB₂-dependent neuroprotection was more pronounced than that conferred by CB₁. These data suggest that BCL modulates only distinct ECS elements like CB₁ and CB₂, and that saffron and cannabinoid receptors could share the same mechanism in order to afford retinal protection.

Both age related macular degeneration (AMD) and light induced retinal damage share the common major role played by oxidative stress in the induction/progression of degenerative events. Light damaged (LD) rats have been widely used as a convenient model to gain insight into the mechanisms of degenerative disease, to enucleate relevant steps and to test neuroprotectants. Among them, saffron has been shown to ameliorate degenerative processes and to regulate many genes and protective pathways. Saffron has been also tested in AMD patients. We extended our analysis to a possible additional effect regulated by saffron and compared in AMD patients a pure antioxidant treatment (Lutein/zeaxanthin) with saffron treatment. Methods: Animal model. Sprague-Dawley (SD) adult rats, raised at 5 lux, were exposed to 1000 lux for 24 h and then either immediately sacrificed or placed back at 5 lux for 7 days recovery period. A group of animals was treated with saffron. We performed in the animal model: (1) SDS-PAGE analysis; (2) Western Blotting (3) Enzyme activity assay (4) Immunolabelling; in AMD patients: a longitudinal open-label study 29 (±5) months in two groups of patients: lutein/zeaxanthin (19) and saffron (23) treated. Visual function was tested every 8 months by ERG recordings in addition to clinical examination. Results: Enzymatic activity of MMP-3 is reduced in LD saffron treated retinas and is comparable to control as it is MMP-3 expression. LD treated retinas do not present “rosettes” and microglia activation and migration is highly reduced. Visual function remains stable in saffron treated AMD patients while deteriorates in the lutein/zeaxanthin group. Conclusion: Our results provide evidence of an additional way of action of saffron treatment confirming the complex nature of neuroprotective activities of its chemical components. Accordingly, long term follow-up in AMD patients reveals an added value of saffron supplementation treatment compared to classical antioxidant protocol.