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.

Modulatory effects of 1,25-dihydroxyvitamin D3 on eye disorders: A critical review.

Many studies have shown that the presence of 1,25-dihydroxyvitamin D3 in the eye is able to modulate inflammatory responses. In fact, it has been demonstrated that topical administration of vitamin D3 inhibits Langerhans cells migration from the central cornea, corneal neovascularization, and production of cytokines (i.e., interleukin-1-6-8) in experimental animals. Moreover, both in vitro and in vivo studies have demonstrated that vitamin D is a potent inhibitor of retinal neovascularization. It has been shown that calcitriol, the biologically active form of vitamin D, inhibits angiogenesis both in cultured endothelial cells and in retinas from guinea pigs with retinoblastoma or oxygen-induced ischemic retinopathy. In addition, it seems that this compound is able to prevent the progression from early to neovascular age-related macular degeneration (AMD) and, at the same time, to down-regulate the characteristic inflammatory cascade at the retinal pigment epithelium-choroid interface due to its anti-inflammatory and immunomodulatory capabilities. Furthermore, 1,25-dihydroxyvitamin D3 and its analogue, 2-methylene-19-nor-1,25-dihydroxyvitamin D3, are able to modulate intraocular pressure (IOP) through gene expression. Several studies have suggested a role in glaucoma and diabetic retinopathy therapies for vitamin D3. In conclusion, this review summarizes our current knowledge on the potential use of vitamin D3 in the protection and treatment of ocular diseases in ophthalmology.

Neuroprotection in Glaucoma: Old and New Promising Treatments.

Glaucoma is a major global cause of blindness, but the molecular mechanisms responsible for the neurodegenerative damage are not clear. Undoubtedly, the high intraocular pressure (IOP) and the secondary ischemic and mechanical damage of the optic nerve have a crucial role in retinal ganglion cell (RGC) death. Several studies specifically analyzed the events that lead to nerve fiber layer thinning, showing the importance of both intra- and extracellular factors. In parallel, many neuroprotective substances have been tested for their efficacy and safety in hindering the negative effects that lead to RGC death. New formulations of these compounds, also suitable for chronic oral administration, are likely to be used in clinical practice in the future along with conventional therapies, in order to control the progression of the visual impairment due to primary open-angle glaucoma (POAG). This review illustrates some of these old and new promising agents for the adjuvant treatment of POAG, with particular emphasis on forskolin and melatonin.

Age-related changes in the kinetics of human lenses: prevention of the cataract.

The crystalline lens is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina and, by changing shape, it adjusts focal distance (accommodation). The three classes of structural proteins found in the lens are α, ß, and γ crystallins. These proteins make up more than 90% of the total dry mass of the eye lens. Other components which can be found are sugars, lipids, water, several antioxidants and low weight molecules. When ageing changes occur in the lens, it causes a gradual reduction in transparency, presbyopia and an increase in the scattering and aberration of light waves as well as a degradation of the optical quality of the eye. The main changes that occur with aging are: 1) reduced diffusion of water from the outside to the inside of the lens and from its cortical to its nuclear zone; 2) crystalline change due to the accumulation of high molecular weight aggregates and insoluble proteins; 3) production of advanced glycation end products (AGEs), lipid accumulation, reduction of reduced glutathione content and destruction of ascorbic acid. Even if effective strategies in preventing cataract onset are not already known, good results have been reached in some cases with oral administration of antioxidant substances such as caffeine, pyruvic acid, epigallocatechin gallate (EGCG), α-lipoic acid and ascorbic acid. Furthermore, methionine sulfoxide reductase A (MSRA) over expression could protect lens cells both in presence and in absence of oxidative stress-induced damage. Nevertheless, promising results have been obtained by reducing ultraviolet-induced oxidative damage.

Relationship between Corneal Temperature and Intraocular Pressure in Healthy Individuals: A Clinical Thermographic Analysis.

Purpose. 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°C in the RE and by 0.48°C in the LE (p < 0.001) and IOP concomitantly significantly increased by 1.13 mmHg and 1.46 mmHg, respectively, in each eye (p < 0.001). After cm-CET, average CT significantly decreased by 0.11°C and 0.20°C, respectively, in the RE and LE (RE p = 0.04; LE p = 0.024), followed by a significant IOP decrease of 2.19 mmHg and 1.54 mmHg, respectively, in each eye (RE p < 0.001; LE p = 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.

Oral Administration of Forskolin, Homotaurine, Carnosine, and Folic Acid in Patients with Primary Open Angle Glaucoma: Changes in Intraocular Pressure, Pattern Electroretinogram Amplitude, and Foveal Sensitivity.

PURPOSE: To evaluate the effects of a food supplement containing forskolin, homotaurine, carnosine, folic acid, vitamins B1, B2, B6, and magnesium in patients with primary open angle glaucoma (POAG) already in treatment and compensated by intraocular pressure (IOP)-lowering drugs, during a period of 12 months. METHODS: Twenty-two patients (44 eyes) with POAG, with their IOP compensated by topical drugs, were enrolled and randomly assigned to the food supplement or control treatment group. The additional food supplement treatment consisted of 2 tablets per day (1 in the morning, 1 in the evening) given for 1 year of a balanced association of homotaurine, Coleus forskohlii root extract, L-carnosine, folic acid, vitamins B1, B2, B6, and magnesium. Pattern Electroretinogram (PERG) amplitude, foveal sensitivity obtained with the visual field analyzer frequency doubling technology, and IOP were detected at enrollment (T0), 3 months (T1), 6 months (T2), 9 months (T3), and 12 months (T4). RESULTS: We observed in treated patients a significant further decrease of IOP and an improvement of PERG amplitude at 6, 9, and 12 months, and foveal sensitivity at 12 months. All values remained substantially stable in control patients. CONCLUSIONS: The results of the present pilot study indicate that the components of the food supplement reach the eye in a detectable manner, as evidenced by the effects on the IOP. Moreover, they suggest a short-term neuroactive effect, as indicated by the improvement of PERG amplitude and foveal sensitivity in treated, but not in control patients.

Biomolecular Modulation of Neurodegenerative Events during Ageing.

The objective is to assess the modulation of retinal and optic nerve degenerative events induced by the combination of α-lipoic acid (ALA) and superoxide dismutase (SOD) in an animal model of ageing. For this study, 24 male Wistar-Harlan strain rats were left to age for up to 24 months. One group of rats was subjected to a diet supplemented with ALA and SOD for 8 weeks, while another group was used as a positive control and not subjected to any dietary treatment. To assess the cytoprotective effects of the antioxidants, a morphological analysis was carried out on sections of retina and optic nerve head, stained with haematoxylin-eosin, followed by an analysis of the modifications to nuclear DNA detected by the TUNEL technique. The lipid peroxidation assay was used to assess the damage induced by oxidative stress at cell membrane level. The molecules involved in apoptosis mediated by oxidative stress, such as caspase-3 and inducible nitric oxide synthase, were also assayed by immunolocalization and western blot. ALA and SOD are able to counteract senile neurodegenerative deterioration to the retina and optic nerve. Indeed, the combination of these antioxidant molecules can reduce oxidative stress levels and thus prevent both nuclear degradation and subsequent cell death.

Role of Electrophysiology in the Early Diagnosis and Follow-Up of Diabetic Retinopathy.

Retinopathy is a severe and common complication of diabetes, representing a leading cause of blindness among working-age people in developed countries. It is estimated that the number of people with diabetic retinopathy (DR) will increase from 126.6 million in 2011 to 191 million by 2030. The pathology seems to be characterized not only by the involvement of retinal microvessels but also by a real neuropathy of central nervous system, similar to what happens to the peripheral nerves, particularly affected by diabetes. The neurophysiological techniques help to assess retinal and nervous (optic tract) function. Electroretinography (ERG) and visual evoked potentials (VEP) allow a more detailed study of the visual function and of the possible effects that diabetes can have on the visual function. These techniques have an important role both in the clinic and in research: the central nervous system, in fact, has received much less attention than the peripheral one in the study of the complications of diabetes. These techniques are safe, repeatable, quick, and objective. In addition, both the ERG (especially the oscillatory potentials and the flicker-ERG) and VEP have proved to be successful tools for the early diagnosis of the disease and, potentially, for the ophthalmologic follow-up of diabetic patients.

Hypobaric hypoxia: effects on contrast sensitivity in high altitude environments.

BACKGROUND: Effects of hypobarism and hypoxia on visual performance and mainly on contrast sensitivity (CS) are well known. The purpose of this study was to compare the adjustments of corneal thickness in hypobaric hypoxia conditions with changes in contrast sensitivity. METHODS: There were 12 healthy, emmetropic subjects assigned to the 14(th) Wing Aircrew based in Pratica di Mare AFB (Rome, Italy) who were evaluated for changes occurring in central corneal thickness (CCT), measured by portable ultrasonic pachymeter, and CS, assessed after reading the standard Pelli-Robson charts, during modification of atmospheric pressure and, therefore, of oxygen partial pressure. RESULTS: Hypobaric hypoxia conditions in pilots raised CCT (550 µm to 600 µm) and reduced CS (1.95 log to 1.05 log) in a statistically significant result. DISCUSSION: The study demonstrated that hypoxia and variations of atmospheric pressure may produce corneal edema, including changes of CCT and, correlatively, CS reduction.

Oral treatment with the melatonin agonist agomelatine lowers the intraocular pressure of glaucoma patients.

PURPOSE: Agomelatine is an agonist of melatonin that is used in the treatment of major depressive disorders. It has also shown an ability to decrease IOP in experiment animals and in normal human subjects. This pilot study addresses for the first time agomelatine effects on the IOP of patients affected by POAG. METHODS: Ten patients affected by hypertensive POAG treated by multiple hypotensive topical drugs and under further treatment with agomelatine (25 mg day(-1) per os) for psychiatric problems, were enrolled. IOP tonometric values were measured at enrolment and after 15 and 30 days of agomelatine supplementation. RESULTS: Agomelatine given orally showed a significant hypotonising effect, stably decreasing IOP by roughly 30% of the enrolment value after 15 and 30 days of treatment. CONCLUSIONS: The hypotonising effect of oral systemic agomelatine at 25 mg day(-1) was able to further decrease IOP in both eyes of all enrolled POAG patients in which multiple drug treatment with anti-glaucoma eye drops had no further effect.

Scotopic microperimetry in the early diagnosis of age-related macular degeneration: preliminary study.

BACKGROUND: Recent clinical studies have shown that, in some degenerative retinal diseases, like age-related macular degeneration (AMD), the sensitivity of the rods decreases more rapidly than the sensitivity of the cones. The aim of this study was to evaluate if there is a correlation between the presence of hard drusen at the macular level and the rod damage responsible for the reduction in scotopic retinal sensitivity in subjects at risk for AMD. METHODS: The authors selected 24 subjects (14 men and 10 women) with an average age of 67.25 ± 5.7 years. Macular hard drusen were present in 50% of the subjects at the fundus oculi exam. The researchers evaluated the retinal sensitivity to light in mesopic and scotopic conditions of each subject with an MP-1 scotopic microperimeter (MP-1S). RESULTS: In subjects with hard drusen in the fundus oculi examination, there was a statistically significant reduction in scotopic retinal sensitivity, while the mesopic retinal sensitivity was not compromised. CONCLUSION: This study revealed how the presence of hard drusen at the macular level is associated with a reduction in scotopic retinal sensitivity compared to a control group of healthy subjects. Retinal functionality in a scotopic setting examined with MP-1S could be useful in early diagnosis of AMD.

Role of Protease-Inhibitors in Ocular Diseases.

It has been demonstrated that the balance between proteases and protease-inhibitors system plays a key role in maintaining cellular and tissue homeostasis. Indeed, its alteration has been involved in many ocular and systemic diseases. In particular, research has focused on keratoconus, corneal wounds and ulcers, keratitis, endophthalmitis, age-related macular degeneration, Sorsby fundus dystrophy, loss of nerve cells and photoreceptors during optic neuritis both in vivo and in vitro models. Protease-inhibitors have been extensively studied, rather than proteases, because they may represent a therapeutic approach for some ocular diseases. The protease-inhibitors mainly involved in the onset of the above-mentioned ocular pathologies are: α2-macroglobulin, α1-proteinase inhibitor (α1-PI), metalloproteinase inhibitor (TIMP), maspin, SERPINA3K, SERPINB13, secretory leukocyte protease inhibitor (SLPI), and calpeptin. This review is focused on the several characteristics of dysregulation of this system and, particularly, on a possible role of proteases and protease-inhibitors in molecular remodeling that may lead to some ocular diseases. Recently, researchers have even hypothesized a possible therapeutic effect of the protease-inhibitors in the treatment of injured eye in animal models.

Age-related visual signal changes induced by hypoxemic hypoxia: a study on aircraft pilots of different ages.

PURPOSE: Exposure to high altitude leads to a series of alterations of higher nervous functions because of hypobaric hypoxia. Sensory systems, mainly the visual one, seem to be particularly involved. This study aimed to assess the effects of hypoxemic hypoxia on the transmission of the visual stimulus simulating a condition of breathing at an altitude of 18,000 feet (5,486 m) through the administration of an air mixture with 10% O2. METHODS: The subjects involved in the study were 98 pilots of military aircraft (male, acclimated, healthy, 20/20 Uncorrected Visual Acuity (UCVA)/Best Corrected Visual Acuity (BCVA), and aged between 26 and 49 years) divided into 2 groups according to age (A: 26-36 years; B: 37-49 years). The visual evoked potentials were initially recorded at sea level (760 mm Hg) and subsequently at a simulated altitude of 18,000 feet (5,486 m) through the administration of an air mixture with 10% O2 that induced a blood saturation of 80% O2 after 15 minutes. The analysis was carried out using two different kinds of stimulus (15' and 60' of arc). The latency and the amplitude of N-75 (N1) and P-100 (P1) waves have been evaluated. Results obtained from visual evoked potentials were analyzed with Student t-test. RESULTS: In the first group (pilots aged 26-36 years), an increase in both latency and amplitude of P-100 wave was observed and in the second group (pilots aged 37-49 years), an increase was found in latency and a significant reduction in amplitude. CONCLUSIONS: The study suggests the existence of a mechanism or a particular anatomic and physiologic condition (probably the neurovascular coupling) that connects the local neuronal activity and the resulting changes in cerebral perfusion. This complex series of events binds together different structures and cell types, and it seems that younger people have a better resistance against the hypoxic insult to the central nervous system because of more efficient compensatory mechanisms.

Role of the dopaminergic system in the development of myopia in children and adolescents.

This review summarizes the experimental evidence that supports the role of dopamine in the regulation of ocular axial growth. The most important functions attributed to dopamine are light adaptation and regulation of the retinal circadian rhythm. An increase of the retinal levels of dopamine activates D1 and D2 dopaminergic receptors present throughout the retina, generating a signal that inhibits axial growth once the eye has reached emmetropization. Researchers induced form-deprivation myopia in animal models in order to assess the different changes of ocular axial growth. Other studies have shown that phenylethylamine is an endogenous precursor-neurotransmitter capable of modulating the activity of dopamine. Considering the role of the dopaminergic system in the development of myopia (in children and adolescents) and the fact that phenylethylamine improves the consequences of a dopamine deficit, it would be interesting to study the effect of phenylethylamine on the regulation of axial growth, which represents the genesis of myopia.

Hypobaric hypoxia: effects on intraocular pressure and corneal thickness.

OBJECTIVE: The purpose of this study focused on understanding the mechanisms underlying ocular hydrodynamics and the changes which occur in the eyes of subjects exposed to hypobaric hypoxia (HH) to permit the achievement of more detailed knowledge in glaucomatous disease. METHODS: Twenty male subjects, aged 32±5 years, attending the Italian Air Force, were enrolled for this study. The research derived from hypobaric chamber, using helmet and mask supplied to jet pilotes connected to oxygen cylinder and equipped with a preset automatic mixer. RESULTS: The baseline values of intraocular pressure (IOP), recorded at T1, showed a mean of 16±2.23 mmHg, while climbing up to 18,000 feet the mean value was 13.7±4.17 mmHg, recorded at T2. The last assessment was performed returning to sea level (T4) where the mean IOP value was 12.8±2.57 mmHg, with a significant change (P<0.05) compared to T1. Pachymetry values related to corneal thickness in conditions of hypobarism revealed a statistically significant increase (P<0.05). CONCLUSIONS: The data collected in this research seem to confirm the increasing outflow of aqueous humor (AH) in the trabecular meshwork (TM) under conditions of HH.

Diabetic retinopathy and pregnancy.

Diabetes mellitus and pregnancy have reciprocal influences between them, therefore diabetes mellitus may complicate the course of pregnancy as well as pregnancy can worsen the performance of diabetes especially at the fundus oculi. Several factors seem to play a role in retinal neovascularization. Actually it's not possible to understand the mechanisms underlying this progression. Moreover chronic hyperglycemia leads to several events such as: the activation of aldose reductase metabolic pathway, the activation of the diacylglycerol-protein kinase C, the non-enzymatic glycation of proteins with formation of advanced glycation endproducts and the increase of hexosamines pathway. Although every structure of the eye can be affected by diabetes, retinal tissue, with all its vessels, is particularly susceptible. Pregnancy may promote the onset of diabetic retinopathy, in about 10 % of cases, as well as contribute to its worsening when already present. The proliferative retinopathy must always be treated; treatment should be earlier in pregnant women compared to non-pregnant women. Pregnancy can also cause macular edema; it spontaneously regresses during the postpartum and therefore does not require immediate treatment. In summary, collaboration between the various specialists is primary to ensure the best outcomes for both mother's health and sight, and fetus' health.

Amblyopia treatment strategies and new drug therapies.

Amblyopia is a unilateral or bilateral reduction of visual acuity secondary to abnormal visual experience during early childhood. It is one of the most common causes of vision loss and monocular blindness and is commonly associated with strabismus, anisometropia, and visual deprivation (in particular congenital cataract and ptosis). It is clinically defined as a two-line difference of best-corrected visual acuity between the eyes. The purpose of this study was to understand the neural mechanisms of amblyopia and summarize the current therapeutic strategies. In particular, the authors focused on the concept of brain plasticity and its implication for new treatment strategies for children and adults with amblyopia.

Curcumin: therapeutical potential in ophthalmology.

Curcumin (diferuloylmethane) is the main curcuminoid of the popular Indian spice turmeric (Curcuma longa). In the last 50 years, in vitro and in vivo experiments supported the main role of polyphenols and curcumin for the prevention and treatment of many different inflammatory diseases and tumors.The anti-inflammatory, antioxidant, and antitumor properties of curcumin are due to different cellular mechanisms: this compound, in fact, produces different responses in different cell types. Unfortunately, because of its low solubility and oral bioavailability, the biomedical potential of curcumin is not easy to exploit; for this reason more attention has been given to nanoparticles and liposomes, which are able to improve curcumin's bioavailability. Pharmacologically, curcumin does not show any dose-limiting toxicity when it is administered at doses of up to 8 g/day for three months. It has been demonstrated that curcumin has beneficial effects on several ocular diseases, such as chronic anterior uveitis, diabetic retinopathy, glaucoma, age-related macular degeneration, and dry eye syndrome. The purpose of this review is to report what has so far been elucidated about curcumin properties and its potential use in ophthalmology.

Psychophysical Exams as Early Indicators of Diabetic Retinopathy.

Retinopathy is a serious and common complication of diabetes that represents the leading cause of blindness, among people of working age, in developed countries. It is estimated that the number of people with diabetic retinopathy (DR) will increase from 126.6 million in 2011 to 191 million by 2030. The visual function that seems to be affected first in the course of DR is probably the contrast sensitivity; in addition, being mainly a macular function, the perception of colour is also compromised. Moreover, the duration of the disease, the levels of glycated haemoglobin (HbA1c) and the presence of cystoid macular oedema are strongly associated with the impairment of fixation stability in patients with diabetes with clinically significant macular oedema, suggesting the possible diagnostic role of microperimetry. The test of contrast sensitivity and the microperimetry and the chromatic sensitivity tests have proved to be useful, safe, reproducible and inexpensive tools to diagnose the disease early.

Intravitreal injections and diabetic macular edema: actual and new therapeutic options.

The management of diabetic macular edema (DME) has been revolutionized in recent years. Focal and focal/ grid laser photocoagulation have been the mainstay of treatment for DME for much time. However, nowadays, there is growing evidence that intravitreal VEGF-inhibitors (combined or not with laser photocoagulation) provide better visual outcome in patients with diabetic retinopathy. Hence, anti-VEGF injections are considered the new gold standard to treat diabetic macular edema and eyes with a reduced visual function. Further studies assessing different treatment regimens are underway to define better clinical care pathways.