Relationship between corneal temperature and i0ntraocular pressure in healthy Individuals. a clinical thermographic analysis

To study the geographical distribution of corneal temperature (CT) and its influence on the intraocular pressure (IOP) of healthy human volunteers. Materials and Methods. Fifteen subjects (7 M, 8 F), 33.8 +/- 17.4 years old, were enrolled in this pilot, cross-sectional study. Measurements of CT were taken after one hour with closed eyelids (CET) or closed eyelids with a cooling mask (cm-CET) and compared to baseline. Results. If compared to baseline, after CET, average CT significantly increased by 0.56 degrees C in the RE and by 0.48 degrees C in the LE (p < 0.001) and IOP concomitantly significantly increased by 1.13 mm Hg and 1.46 mm Hg, respectively, in each eye (p < 0.001). After cm-CET, average CT significantly decreased by 0.11 degrees C and 0.20 degrees C, respectively, in the RE and LE (RE p = 0.04; LE p = 0.024), followed by a significant IOP decrease of 2.19 mm Hg and 1.54 mm Hg, respectively, in each eye (RE p < 0.001; LE = 0.0019). Conclusion. Significant variations of CT occurred after CET and cm-CET and were directly correlated with significant differences of IOP. It can be speculated that both oxidative stress and sympathetic nerve fiber stimulation by temperature oscillations may affect the regulation of AH vortex flow and turnover, thus influencing IOP values

Neovascularization in alkali-burned rabbit cornea

Objective: To study the neovascularization in regenerating and proliferating corneal cells following a standard alkali injury in rabbit eye. Methods: Three and six weeks after the creation of an alkali burn in the center of the right cornea of six albino rabbits, the animals were killed and histological sections from the cornea of both eyes were stained, photographed and studied for a possible formation of a neovascularization. The photographs were examined using the Quantimet image analyzer (Leica) and statistical analysis of the data was performed. Results: Sections of the injured cornea showed the formation of neovessels in the epithelial and superficial stromal layers. The neovascularization is present after 3 weeks of the corneal injury. After 6 weeks from the corneal alkali burn, neovessels are increased. Conclusions: There is a growing body of evidence suggesting that vascular abnormalities may play a crucial rolein several ocular diseases. To improve our knowledge of the vascular involvement in these conditions, there is a need for a non-invasive imaging modality capable of assessing microcirculation within ocular tissue beds both in vitro and in vivo. This study shows that ultra-high sensitive optical microangiography, associated with other experimental techniques, is an adequate technique to visualize the eye surface microcirculations and to quantify microvascular vessel density under both normal and physio-pathological conditions

An Association of Vitamins A and E with Hyaluronic and Lactobionic Acids may Prevent Molecular Changes Associated with Keratocyte to Myofibroblast Transition

Inflammatory events in the corneal stroma may activate keratocytes and trigger their transition towards myofibroblasts, which now produce different extracellular matrix (ECM) proteins thus causing corneal opacification.Corneal haze is a frequent side effect after photorefractive keratectomy (PRK) to correct high myopia.Currently, a preventive treatment with mitomycin-c can be used to limit the occurrence of this phenomenon. However, mitomycin-c is a toxic drug, not devoid of side effects, which may occasionally involve the corneal endothelium. Therefore, we have searched for a less risky, natural way, to prevent keratocytes transition. To this purpose, we have used as markers of the phenotype switch the proteins lumican (highly expressed by keratocytes and much less by myofibroblasts) and smooth muscle actin (αSMA) (highly expressed by myofibroblasts and poorly found in keratocytes), beside Fibronectin (Fn), the expression of which is also increased by transforming growth factor-beta (TGFβ treatment. Treatment of human keratocytes with TGFβ was used to induce the protein shift. Among different possible candidates, we have found that vitamins A and E, hyaluronic and lactobionic acids may prevent, either alone, or much better in association, the shift in the ratio between lumican and αSMA and the increased Fn expression. In conclusion, it could be speculated that topic treatment of the ocular surface with an association of these four compounds could be able to prevent or at least limit the occurrence of post-PRK corneal haze, with the additional advantage of lubrication, hydration and antioxidant defense exerted by these molecules

Increased efficacy of dietary supplement containing wax ester-rich marine oil and xanthophylls in a mouse model of dry macular degeneration

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

A Topical Formulation of Melatoninergic Compounds Exerts Strong Hypotensive and Neuroprotective Effects in a Rat Model of Hypertensive Glaucoma

Melatonin is of great importance for regulating several eye processes, including pressure homeostasis. Melatonin in combination with agomelatine has been recently reported to reduce intraocular pressure (IOP) with higher efficacy than each compound alone. Here, we used the methylcellulose (MCE) rat model of hypertensive glaucoma, an optic neuropathy characterized by the apoptotic death of retinal ganglion cells (RGCs), to evaluate the hypotensive and neuroprotective efficacy of an eye drop nanomicellar formulation containing melatonin/agomelatine. Eye tissue distribution of melatonin/agomelatine in healthy rats was evaluated by HPLC/MS/MS. In the MCE model, we assessed by tonometry the hypotensive efficacy of melatonin/agomelatine. Neuroprotection was revealed by electroretinography; by levels of inflammatory and apoptotic markers; and by RGC density. The effects of melatonin/agomelatine were compared with those of timolol (a beta blocker with prevalent hypotensive activity) or brimonidine (an alpha 2 adrenergic agonist with potential neuroprotective efficacy), two drugs commonly used to treat glaucoma. Both melatonin and agomelatine penetrate the posterior segment of the eye. In the MCE model, IOP elevation was drastically reduced by melatonin/agomelatine with higher efficacy than that of timolol or brimonidine. Concomitantly, gliosis-related inflammation and the Bax-associated apoptosis were partially prevented, thus leading to RGC survival and recovered retinal dysfunction. We suggest that topical melatoninergic compounds might be beneficial for ocular health

Hypotensive Effect of Nanomicellar Formulation of Melatonin and Agomelatine in a Rat Model: Significance for Glaucoma Therapy

Background: Melatoninergic agents are known to reduce intraocular pressure (IOP). The present study was performed to evaluate the effect of nanomicellar formulations of melatoninergic agents on IOP in the rat. Methods: Tonometry was used to measure IOP in eyes instilled with melatonin or agomelatine. Ocular hypertension was induced by the injection of methylcellulose in the anterior chamber. Results: Melatonin formulated in nanomicelles had a longer lasting hypotonizing effect on IOP with respect to melatonin in saline. Nanomicellar formulations of melatonin and agomelatine, either alone or in combination, had lowering effects that did not depend on their concentration or their combination, which, however, resulted in an increased duration of the hypotonizing effect. The duration of the lowering effect was further increased by the addition of lipoic acid. Conclusions: We demonstrated the effective hypotonizing activity of melatonin and agomelatine in combination with lipoic acid. Although results in animals cannot be directly translated to humans, the possibility of developing novel therapeutical approaches for patients suffering from hypertensive glaucoma should be considered

Molecular Mechanisms Mediating Antiangiogenic Action of the Urokinase Receptor-Derived Peptide UPARANT in Human Retinal Endothelial Cells

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Structural Basis for Agonistic Activity and Selectivity toward Melatonin Receptors hMT1 and hMT2

: Glaucoma, a major ocular neuropathy originating from a progressive degeneration of retinal ganglion cells, is often associated with increased intraocular pressure (IOP). Daily IOP fluctuations are physiologically influenced by the antioxidant and signaling activities of melatonin. This endogenous modulator has limited employment in treating altered IOP disorders due to its low stability and bioavailability. The search for low-toxic compounds as potential melatonin agonists with higher stability and bioavailability than melatonin itself could start only from knowing the molecular basis of melatonergic activity. Thus, using a computational approach, we studied the melatonin binding toward its natural macromolecular targets, namely melatonin receptors 1 (MT1) and 2 (MT2), both involved in IOP signaling regulation. Besides, agomelatine, a melatonin-derivative agonist and, at the same time, an atypical antidepressant, was also included in the study due to its powerful IOP-lowering effects. For both ligands, we evaluated both stability and ligand positioning inside the orthosteric site of MTs, mapping the main molecular interactions responsible for receptor activation. Affinity values in terms of free binding energy (ΔGbind) were calculated for the selected poses of the chosen compounds after stabilization through a dynamic molecular docking protocol. The results were compared with experimental in vivo effects, showing a higher potency and more durable effect for agomelatine with respect to melatonin, which could be ascribed both to its higher affinity for hMT2 and to its additional activity as an antagonist for the serotonin receptor 5-HT2c, in agreement with the in silico results

the urokinase receptor derived peptide uparant recovers dysfunctional electroretinogram and blood retinal barrier leakage in a rat model of diabetes

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Restored retinal physiology after administration of niacin with citicoline in a mouse model of hypertensive glaucoma

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