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This review highlights the therapeutic potential of epigallocatechin gallate (EGCG) and forskolin in managing retinal diseases, with a focus on glaucoma, age-related macular degeneration (AMD), and diabetic retinopathy. EGCG, a potent polyphenol from green tea, exhibits significant antioxidant, anti-inflammatory, and neuroprotective effects, making it a promising candidate for reducing oxidative stress and inflammation in ocular tissues. Forskolin, a diterpene from Coleus forskohlii, increases cyclic AMP (cAMP) levels, which helps lower intraocular pressure (IOP) and provides neuroprotection. Both compounds target critical pathways involved in retinal disease progression, including oxidative stress, mitochondrial dysfunction, and inflammation, offering complementary therapeutic benefits. This review consolidates preclinical and clinical studies, highlighting the potential of EGCG and forskolin as adjunctive or alternative treatments for retinal diseases. Future research should explore the synergistic effects of these compounds, particularly in combination therapies aimed at addressing multiple pathogenic mechanisms in retinal health.

Oxidative stress, caused by the formation of free radicals, such as reactive oxygen species (ROS), leads to cell and tissue degradation, contributing to various diseases and aging. While oxygen is essential for aerobic organisms, it inevitably causes oxidative stress. Antioxidants protect against damage from free radicals, and oxidative stress arises when an imbalance occurs between free radical production and antioxidant defenses. However, when investigating whether an excess of antioxidants, almost eliminating oxidative stress, could benefit aging and disease susceptibility, it was observed that a basic level of oxidative stress appears necessary to maintain the correct homeostasis of tissues and organs and life in general. Therefore, this review aimed to compile the most significant and recent papers characterizing and describing the dual role of oxygen as a molecule essential for life and as a precursor of oxidative stress, which can be detrimental to life. We conducted targeted searches in PubMed and Google browsers to gather all relevant papers. We then focused on the eye, an organ particularly vulnerable due to its high metabolic activity combined with direct exposure to light and environmental pollutants, which produces a substantial number of free radicals (mainly ROS). We present a curated selection of relevant literature describing the main ocular pathologies of the posterior and anterior segments of the eye, highlighting oxidative stress as a significant contributing factor. Additionally, we report how endogenous and exogenous antioxidants can mitigate the development and progression of these diseases. Finally, we consider a frequently overlooked aspect: the balance between oxidants and antioxidants in maintaining the homeostatic equilibrium of tissues and organs. It is widely recognized that when oxidants overwhelm antioxidants, oxidative stress occurs, leading to negative consequences for the organism's homeostasis. However, we emphasize that a similarly dangerous situation can arise when the presence of antioxidants overwhelms the production of free radicals, drastically reducing their amount and adversely affecting aging and longevity. Unfortunately, no specific studies have addressed this particular situation in the eye.

This review explores the connection between the ocular surface microbiome and glaucoma, highlighting its impact on disease progression. Beginning with an overview of global glaucoma significance, it emphasizes the importance of understanding the cellular characteristics and microbiology of the ocular microbiome. A search was conducted on the PubMed and Cochrane Library databases using the phrase “ocular microbiome glaucoma”. 0 records were returned from the Cochrane Library while 21 were returned from PubMed. A total of 21 results were retrieved from 2017 to 2024. This comprised one opinion paper, four original research articles, and 16 reviews. This review covered the anatomy of the ocular surface, advanced analysis methods, and the ocular microbiome. It also delved into dysbiosis in glaucoma, addressing altered microbial communities and their potential role in disease progression. The intricate interplay between the ocular microbiome and the host’s immune system is explored, emphasizing crosstalk and inflammatory responses. The review concludes by discussing therapeutic implications, including modulating ocular microbiota and potential future treatment strategies. Understanding the microbiome in healthy and glaucomatous eyes can help researchers and clinicians in innovative approaches to ocular health.

Gabapentin (GBP) was originally developed as a potential agonist for Gamma-Amino-Butyric-Acid (GABA) receptors, aiming to inhibit the activation of pain-signaling neurons. Contrary to initial expectations, it does not bind to GABA receptors. Instead, it exhibits several distinct pharmacological activities, including: (1) binding to the alpha-2-delta protein subunit of voltage-gated calcium channels in the central nervous system, thereby blocking the excitatory influx of calcium; (2) reducing the expression and phosphorylation of CaMKII via modulation of ERK1/2 phosphorylation; (3) inhibiting glutamate release and interfering with the activation of NMDA receptors; (4) enhancing GABA synthesis; (5) increasing cell-surface expression of δGABA_A receptors, contributing to its antinociceptive, anticonvulsant, and anxiolytic-like effects. Additionally, GBP displays (6) inhibition of NF-kB activation and subsequent production of inflammatory cytokines, and (7) stimulation of the purinergic adenosine A1 receptor, which supports its anti-inflammatory and wound-healing properties. Initially approved for treating seizures and postherpetic neuralgia, GBP is now broadly used for various conditions, including psychiatric disorders, acute and chronic neuropathic pain, and sleep disturbances. Recently, as an eye drop formulation, it has also been explored as a therapeutic option for ocular surface discomfort in conditions such as dry eye, neurotrophic keratitis, corneal ulcers, and neuropathic ocular pain. This review aims to summarize the evidence supporting the molecular effects of GBP, with a special emphasis on its applications in ocular surface diseases.

IntroductionMuch interest has been addressed to antioxidant dietary supplements that are known to lower the risk of developing glaucoma or delay its progression. Among them, niacin and citicoline protect retinal ganglion cells (RGCs) from degeneration by targeting mitochondria, though at different levels. A well-established mouse model of RGC degeneration induced by experimental intraocular pressure (IOP) elevation was used to investigate whether a novel combination of niacin/citicoline has better efficacy over each single component in preserving RGC health in response to IOP increase.MethodsOcular hypertension was induced by an intracameral injection of methylcellulose that clogs the trabecular meshwork. Electroretinography and immunohistochemistry were used to evaluate RGC function and density. Oxidative, inflammatory and apoptotic markers were evaluated by Western blot analysis.ResultsThe present results support an optimal efficacy of niacin with citicoline at their best dosage in preventing RGC loss. In fact, about 50% of RGCs were spared from death leading to improved electroretinographic responses to flash and pattern stimulation. Upregulated levels of oxidative stress and inflammatory markers were also consistently reduced by almost 50% after niacin with citicoline thus providing a significant strength to the validity of their combination.ConclusionNiacin combined with citicoline is highly effective in restoring RGC physiology but its therapeutic potential needs to be further explored. In fact, the translation of the present compound to humans is limited by several factors including the mouse modeling, the higher doses of the supplements that are necessary to demonstrate their efficacy over a short follow up period and the scarce knowledge of their transport to the bloodstream and to the eventual target tissues in the eye.

Melatonin is a ubiquitous molecule found in living organisms, ranging from bacteria to plants and mammals. It possesses various properties, partly due to its robust antioxidant nature and partly owed to its specific interaction with melatonin receptors present in almost all tissues. Melatonin regulates different physiological functions and contributes to the homeostasis of the entire organism. In the human eye, a small amount of melatonin is also present, produced by cells in the anterior segment and the posterior pole, including the retina. In the eye, melatonin may provide antioxidant protection along with regulating physiological functions of ocular tissues, including intraocular pressure (IOP). Therefore, it is conceivable that the exogenous topical administration of sufficiently high amounts of melatonin to the eye could be beneficial in several instances: for the treatment of eye pathologies like glaucoma, due to the IOP-lowering and neuroprotection effects of melatonin; for the prevention of other dysfunctions, such as dry eye and refractive defects (cataract and myopia) mainly due to its antioxidant properties; for diabetic retinopathy due to its metabolic influence and neuroprotective effects; for macular degeneration due to the antioxidant and neuroprotective properties; and for uveitis, mostly owing to anti-inflammatory and immunomodulatory properties. This paper reviews the scientific evidence supporting the use of melatonin in different ocular districts. Moreover, it provides data suggesting that the topical administration of melatonin as eye drops is a real possibility, utilizing nanotechnological formulations that could improve its solubility and permeation through the eye. This way, its distribution and concentration in different ocular tissues may support its pleiotropic therapeutic effects.

Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.

Age-related macular degeneration (AMD) is nowadays considered among the retinal diseases whose clinical management lacks established treatment approaches, mainly for its atrophic (dry) form. In this respect, the use of dietary patterns enriched in omega-3 and antioxidant xanthophylls has emerged as a promising approach to counteract dry AMD progression although the prophylactic potential of omega-3 of fish origin has been discussed. Whether enriched availability of omega-3 and xanthophylls may increase the effectiveness of diet supplementation in preventing dry AMD remains to be fully established. The present study aims at comparing the efficacy of an existing orally administered formulation based on lutein and fish oil, as a source of omega-3, with a novel formulation providing the combination of lutein and astaxanthin with Calanus oil (COil), which contains omega-3 together with their precursors policosanols. Using a mouse model of dry AMD based on subretinal injection of polyethylene glycol (PEG)-400, we assessed the comparative efficacy of both formulations on PEG-induced major hallmarks including oxidative stress, inflammation, glial reactivity and outer retinal thickness. Dietary supplementation with both mixtures has been found to exert a significant antioxidant and anti-inflammatory activity as reflected by the overall amelioration of the PEG-induced pathological hallmarks. Noteworthy, the formulation based on COil appeared to be more protective than the one based on fish oil, presumably because of the higher bioavailability of omega-3 in COil. These results support the use of dietary supplements combining omega-3 and xanthophylls in the prevention and treatment of AMD and suggest that the source of omega-3 might contribute to treatment efficacy.

In this review, we aim to provide an overview of the recent findings about the treatment of neovascular retinal diseases. The use of conventional drugs and nutraceuticals endowed with antioxidant and anti-inflammatory properties that may support conventional therapies will be considered, with the final aim of achieving risk reduction (prevention) and outcome improvement (cooperation between treatments) of such sight-threatening proliferative retinopathies. For this purpose, we consider a medicinal product one that contains well-defined compound(s) with proven pharmacological and therapeutic effects, usually given for the treatment of full-blown diseases. Rarely are prescription drugs given for preventive purposes. A dietary supplement refers to a compound (often an extract or a mixture) used in the prevention or co-adjuvant treatment of a given pathology. However, it must be kept in mind that drug–supplement interactions may exist and might affect the efficacy of certain drug treatments. Moreover, the distinction between medicinal products and dietary supplements is not always straightforward. For instance, melatonin is formulated as a medicinal product for the treatment of sleep and behavioral problems; at low doses (usually below 1 mg), it is considered a nutraceutical, while at higher doses, it is sold as a psychotropic drug. Despite their lower status with respect to drugs, increasing evidence supports the notion of the beneficial effects of dietary supplements on proliferative retinopathies, a major cause of vision loss in the elderly. Therefore, we believe that, on a patient-by-patient basis, the administration of nutraceuticals, either alone or in association, could benefit many patients, delaying the progression of their disease and likely improving the efficacy of pharmaceutical drugs.

Meldonium (MID) is a synthetic drug designed to decrease the availability of L-carnitine—a main player in mitochondrial energy generation—thus modulating the cell pathways of energy metabolism. Its clinical effects are mostly evident in blood vessels during ischemic events, when the hyperproduction of endogenous carnitine enhances cell metabolic activities, leading to increased oxidative stress and apoptosis. MID has shown vaso-protective effects in model systems of endothelial dysfunction induced by high glucose or by hypertension. By stimulating the endothelial nitric oxide synthetase (eNOS) via PI3 and Akt kinase, it has shown beneficial effects on the microcirculation and blood perfusion. Elevated intraocular pressure (IOP) and endothelial dysfunction are major risk factors for glaucoma development and progression, and IOP remains the main target for its pharmacological treatment. IOP is maintained through the filtration efficiency of the trabecular meshwork (TM), a porous tissue derived from the neuroectoderm. Therefore, given the effects of MID on blood vessels and endothelial cells, we investigated the effects of the topical instillation of MID eye drops on the IOP of normotensive rats and on the cell metabolism and motility of human TM cells in vitro. Results show a significant dose-dependent decrease in the IOP upon topic treatment and a decrease in TM cell motility in the wound-healing assay, correlating with an enhanced expression of vinculin localized in focal adhesion plaques. Motility inhibition was also evident on scleral fibroblasts in vitro. These results may encourage a further exploration of MID eye drops in glaucoma treatment.

In diabetic retinopathy (DR), high blood glucose drives chronic oxidative stress and inflammation that trigger alterations of the neurovascular balance finally resulting in vascular abnormalities and retinal cell death, which converge towards altered electroretinogram (ERG). In the last years, a growing body of preclinical evidence has suggested that nutrients with anti-inflammatory/antioxidant properties can be able to hamper DR progression since its very early stages. In the present study, we used a streptozotocin-induced rat model of DR, which mimics most aspects of the early stages of human DR, to test the preventive efficacy of a novel compound containing cyanidin-3-glucoside (C3G), verbascoside and zinc as nutrients with antioxidant and anti-inflammatory properties. Western blot, immunofluorescence and electroretinographic analyses demonstrated a dose-dependent inhibition of oxidative stress- and inflammation-related mechanisms, with a significant counterpart in preventing molecular mechanisms leading to DR-associated vasculopathy and its related retinal damage. Preventive efficacy of the compound on dysfunctional a- and b-waves was also demonstrated by electroretinography. The present demonstration that natural compounds, possibly as a consequence of vascular rescue following ameliorated oxidative stress and inflammation, may prevent the apoptotic cascade leading to ERG dysfunction, adds further relevance to the potential application of antioxidants as a preventive therapy to counteract DR progression.

Background: Reactive oxygen species (ROS) accumulation plays a pivotal role in the onset of cell damage induced by hyperglycemia and represents one of the major factors in the pathogenesis of diabetic retinopathy. In this study, we tested the antioxidants cyanidin-3-O-glucoside (C3G) and verbascoside (Verb) in the protection of retinal endothelium against glucose toxicity “in vitro”. Methods: Increasing amounts (5–50 μM) of C3G, Verb or the combination of both compounds were tested in Human Retinal Endothelial Cells (HREC) grown with normal glucose (5 mM, NG) or high glucose (25 mM, HG). Results: Reduced cell viability and enhanced ROS levels (evaluated by MTT and H2DCFDA assays, respectively) in HG-stimulated HREC were restored by C3G and Verb in a dose-dependent manner, achieving the maximum protection in the presence of both compounds. Moreover, co-treatment with C3G and Verb worked better than each single molecule alone in the prevention of the disruption of blood-retinal-barrier-like properties by HG in a confluent HREC monolayer, as assessed by trans endothelial electrical resistance (TEER) and Na-Fluorescein permeability assays. Accordingly, C3G and Verb together also better counteracted the HG-induced down-regulation of the tight junction membrane proteins Zonula Occludens-1 and VE-Cadherin evaluated by immunocytochemical and Western blot analyses. Conclusions: In conclusion, our data indicate that C3G and Verb could efficiently protect the retinal endothelium against high glucose damage.

Purpose: The purpose of this study is to investigate the effects of the treatment with eye-drops based on a combination of antioxidant and mucomimetic molecules, namely 0.1% alpha-lipoic acid (ALA) and 0.3% hydroxy-propyl-methylcellulose (HPMC) on the ocular surface of diabetic patients with dry eye symptoms. Methods: Seventy patients, 42 M and 28 F, aged from 50 to79 years (mean 62.1 ± 10.5), affected by type II diabetes mellitus, were enrolled and divided in two groups treated for 2 months as follows: Group 1 (35 patients), received topical ALA/HPMC three times a day, Group 2 (35 patients) received topical HPMC (0.3%) alone, three times a day. The main outcome measures were: Ocular Surface Disease Index (OSDI), tear film break-up time (TBUT), corneal fluorescein staining, Schirmer I test, corneal sensitivity. An examination of tear film morphology with confocal microscopy was carried out in a subset of patients of each group at baseline and after two months. Statistical analysis was performed with t-test for the parametric data and Mann-Whitney U-test or chi-squared test for the nonparametric data. Results: Both treatments resulted in significant improvements of BUT, OSDI and tear film morphology, although the improvements observed in group 1 showed a higher trend than what observed for group 2. Moreover, only in group 1 a significant improvement was visible for corneal staining, and no significant improvements were observed in any group for Schirmer I and sensitivity. Conclusions: These results confirmed the efficacy of HPMC in the treatment of diabetic dry eye and indicated that the addition of a strong self-regenerating antioxidant like ALA may give a distinctive advantage for the healing of corneal defects (as evidenced by corneal staining), beside improving HPMC efficacy on three other parameters (BUT, OSDI score, tear morphology). Therefore, the addition of a strong antioxidant like ALA can be helpful in preventing or treating ocular surface defects in diabetic patients, in which the oxidative damage is predominant.

The aim of this study was to compare in vitro the protective and antioxidant properties of lutein and astaxanthin on human primary corneal epithelial cells (HCE-F). To this purpose, HCE-F cells were irradiated with a blue-violet light lamp (415–420 nm) at different energies (20 to 80 J/cm2). Lutein and astaxanthin (50 to 250 μM) were added to HCE-F right before blue-violet light irradiation at 50 J/cm2. Viability was evaluated by the CKK-8 assay while the production of reactive oxygen species (ROS) by the H2DCF-DA assay. Results have shown that the viability of HCE-F cells decreased at light energies from 20 J/cm2 to 80 J/cm2, while ROS production increased at 50 and 80 J/cm2. The presence of lutein or astaxanthin protected the cells from phototoxicity, with lutein slightly more efficient than astaxanthin also on the blunting of ROS, prevention of apoptotic cell death and modulation of the Nrf-2 pathway. The association of lutein and astaxanthin did not give a significant advantage over the use of lutein alone. Taken together, these results suggest that the association of lutein and astaxanthin might be useful to protect cells of the ocular surface from short (lutein) and longer (astaxanthin) wavelengths, as these are the most damaging radiations hitting the eye from many different LED screens and solar light.