Microbiome Dysbiosis: A Pathological Mechanism at the Intersection of Obesity and Glaucoma.

The rate at which obesity is becoming an epidemic in many countries is alarming. Obese individuals have a high risk of developing elevated intraocular pressure and glaucoma. Additionally, glaucoma is a disease of epidemic proportions. It is characterized by neurodegeneration and neuroinflammation with optic neuropathy and the death of retinal ganglion cells (RGC). On the other hand, there is growing interest in microbiome dysbiosis, particularly in the gut, which has been widely acknowledged to play a prominent role in the etiology of metabolic illnesses such as obesity. Recently, studies have begun to highlight the fact that microbiome dysbiosis could play a critical role in the onset and progression of several neurodegenerative diseases, as well as in the development and progression of several ocular disorders. In obese individuals, gut microbiome dysbiosis can induce endotoxemia and systemic inflammation by causing intestinal barrier malfunction. As a result, bacteria and their metabolites could be delivered via the bloodstream or mesenteric lymphatic vessels to ocular regions at the level of the retina and optic nerve, causing tissue degeneration and neuroinflammation. Nowadays, there is preliminary evidence for the existence of brain and intraocular microbiomes. The altered microbiome of the gut could perturb the resident brain-ocular microbiome ecosystem which, in turn, could exacerbate the local inflammation. All these processes, finally, could lead to the death of RGC and neurodegeneration. The purpose of this literature review is to explore the recent evidence on the role of gut microbiome dysbiosis and related inflammation as common mechanisms underlying obesity and glaucoma.

Poly 2-methacryloyloxyethyl Phosphorylcholine Protects Corneal Cells and Contact Lenses from Desiccation Damage.

SIGNIFICANCE: Contact lens (CL) wearing may cause discomfort and eye dryness. We describe here the efficacy of a synthetic polymer in protecting both the corneal epithelial cells and the CL from desiccation damage. Artificial tears containing this polymer might be helpful to treat or prevent ocular surface damage in CL wearers. PURPOSE: We aimed to investigate the protective effects of the synthetic polymer 2-methacryloyloxyethyl phosphorylcholine (poly-MPC) on corneal epithelial cells and CLs subjected to desiccation damage. METHODS: The interaction of poly-MPC with the cell membrane was evaluated on human primary corneal epithelial cells (HCE-F) by the sodium dodecyl sulfate damage protection assay or the displacement of the cell-binding lectin concanavalin A (ConA). Survival in vitro of HCE-F cells and ex vivo of porcine corneas exposed to desiccating conditions after pre-treatment with poly-MPC or hyaluronic acid (HA), hypromellose (HPMC), and trehalose was evaluated by a colorimetric assay. Soft CLs were soaked overnight in a solution of poly-MPC/HPMC and then let dry in ambient air. Contact lens weight, morphology, and transparency were periodically registered until complete dryness. RESULTS: Polymer 2-methacryloyloxyethyl phosphorylcholine and HPMC were retained on the HCE-F cell membrane more than trehalose or HA. Polymer 2-methacryloyloxyethyl phosphorylcholine, HA, and HPMC either alone or in association protected corneal cells from desiccation significantly better than did trehalose alone or in association with HA. Contact lens permeation by poly-MPC/HPMC preserved better their shape and transparency than did saline. CONCLUSIONS: Polymer 2-methacryloyloxyethyl phosphorylcholine coats and protects corneal epithelial cells and CLs from desiccation damage more efficiently compared with trehalose and as good as other reference compounds.

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.

Phenotypic characterization of the SIRC (Statens Seruminstitut Rabbit Cornea) cell line reveals a mixed epithelial and fibroblastic nature.

The aim of the present study was to investigate, in the Statens Seruminstitut Rabbit Cornea (SIRC) cell line, the presence of epithelial and fibroblastic markers, comparing their levels with those of the human Retinal Pigmented Epithelial (ARPE-19) cell line, and the Human Keratocyte (HK) cell line, respectively. SIRC cells, often described as of epithelial origin, are used as a corneal epithelial barrier model to study the permeability of ophthalmic drugs. However, they show a morphology that is more consistent with a fibroblastic cell phenotype, similar to corneal keratocytes. Our comparative analyses of cell type specific markers demonstrated that SIRC do not express cytokeratins 19 and 16 (typical of ARPE-19) and cytokeratin 9 (typical of HK); they do express cytokeratins 3 and 18 common to all three cell lines, and cytokeratin 12 typical of ARPE-19. Tight junction proteins were absent in HK, and lower in SIRC than in ARPE-19. All cell lines expressed the markers lumican and vimentin, with SIRC expressing intermediate levels between HK and ARPE-19; alpha-SMA was highly expressed in all lines. These markers, considered typical of fibroblasts, can be, however, expressed by epithelial cells during wound healing. These results might suggest that long-term in vitro cultivation of cell lines leads to a derangement of their specific phenotype, most likely due to genetic and epigenetic factors. This could be the reason why SIRC cells came to exhibit a hybrid nature between epithelial and fibroblastic cells.

Age-Related Dry Eye Lactoferrin and Lactobionic Acid.

Dry eye is the most prominent pathology among those involving the ocular surface: a decrease of the aqueous (less frequent) or the lipid (more frequent) component of the tear film is the cause of the diminished stability of tears that is observed in this pathology. Dry eye shows a clear distribution linked to both sex (being more frequent among women) and age (increasing with aging). Therefore, specific treatments taking into account the etiology of the disease would be desired. The role of lactoferrin and its functional mimetic lactobionic acid are reported here as a possible remedy for age-related dry eye.

N-hydroxymethylglycinate with EDTA is an efficient eye drop preservative with very low toxicity: an in vitro comparative study.

PURPOSE: Preservatives are used in multi-dose ophthalmic topical medications in order to prevent contamination by bacteria and fungi. However, prolonged use of preserved eye drops, as it may happen in dry eye or glaucoma, may damage cells of the ocular surface. Therefore, an important goal is to find preservatives with low toxicity which are mild to host cells, still able to prevent drug contamination so to maintain their sterility and efficacy. Hence, aim of this study has been to compare the relative toxicity on a rabbit corneal cell line of a new preservative, made by the association of N-hydroxy-methyl-glycinate (NIG) with disodium-ethylene diamine tetra-acetate (EDTA), with other known and widely used eye-drops preservatives. MATERIALS AND METHODS: Rabbit corneal cells (SIRC) were tested either in 96-well plates or in suspension culture. Treatments with preservatives (used at known bacteriostatic concentrations) included: benzalkonium chloride (BAK), polyquaternium-1 (PQ-1), sodium perborate (SP: NaBO3 * H2O), and NIG ± EDTA at different concentrations (0.001% and 0.002%), and different treatment times (from 30 minutes to 120 hours). At the end of treatment, cell survival was evaluated by a specific spectrophotometric method through the metabolic conversion of MTT [3-(4,5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide] into formazan crystals. RESULTS: Almost no cell toxicity was evident for NIG and SP at either concentration (0.001% or 0.002%), while a low toxicity was observed for PQ-1 (62% at the highest dose at 120 hours). BAK, as expected, showed the highest toxicity (60-80% at 30 minutes, and over 90% from eight hours onward). EDTA 0.1% alone or in combination with NIG 0.002%, showed no toxicity at 24 hours, and even resulted in cell growth promotion (46% and 38%, respectively), after 48 hours of treatment. CONCLUSIONS: These data show that the new preservative NIG/EDTA, at doses known to have effective antimicrobial properties, has a very low toxicity on corneal cells, and so it can be safely used in multi-dose eye drops.

Role of Perturbated Hemostasis in MASLD and Its Correlation with Adipokines.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, making it one of the most prevalent chronic liver disorders. MASLD encompasses a range of liver pathologies, from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) with inflammation, hepatocyte damage, and fibrosis. Interestingly, the liver exhibits close intercommunication with fatty tissue. In fact, adipose tissue could contribute to the etiology and advancement of MASLD, acting as an endocrine organ that releases several hormones and cytokines, with the adipokines assuming a pivotal role. The levels of adipokines in the blood are altered in people with MASLD, and recent research has shed light on the crucial role played by adipokines in regulating energy expenditure, inflammation, and fibrosis in MASLD. However, MASLD disease is a multifaceted condition that affects various aspects of health beyond liver function, including its impact on hemostasis. The alterations in coagulation mechanisms and endothelial and platelet functions may play a role in the increased vulnerability and severity of MASLD. Therefore, more attention is being given to imbalanced adipokines as causative agents in causing disturbances in hemostasis in MASLD. Metabolic inflammation and hepatic injury are fundamental components of MASLD, and the interrelation between these biological components and the hemostasis pathway is delineated by reciprocal influences, as well as the induction of alterations. Adipokines have the potential to serve as the shared elements within this complex interrelationship. The objective of this review is to thoroughly examine the existing scientific knowledge on the impairment of hemostasis in MASLD and its connection with adipokines, with the aim of enhancing our comprehension of the disease.

Exploring public interest in gut microbiome dysbiosis, NAFLD, and probiotics using Google Trends.

Scientific interest related to the role of gut microbiome dysbiosis in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has now been established and is constantly growing. Therefore, balancing dysbiosis, through probiotics, would be a potential therapy. In addition to scientific interest, on the other hand, it is important to evaluate the interest in these topics among the population. This study aimed to analyze, temporally and geographically, the public's interest in gut microbiome dysbiosis, NAFLD, and the use of gut probiotics. The most widely used free tool for analyzing online behavior is Google Trends. Using Google Trends data, we have analyzed worldwide volume searches for the terms "gut microbiome", "dysbiosis", "NAFLD" and "gut probiotic" for the period from 1, January 2007 to 31 December 2022. Google's relative search volume (RSV) was collected for all terms and analyzed temporally and geographically. The RSV for the term "gut microbiome" has a growth rate of more than 1400% followed, by "gut probiotics" (829%), NAFLD (795%), and "dysbiosis" (267%) from 2007 to 2012. In Australia and New Zealand, we found the highest RSV score for the term "dysbiosis" and "gut probiotics". Moreover, we found the highest RSV score for the term "NAFLD" in the three countries: South Korea, Singapore, and the Philippines. Google Trends analysis showed that people all over the world are interested in and aware of gut microbiome dysbiosis, NAFLD, and the use of gut probiotics. These data change over time and have a geographical distribution that could reflect the epidemiological worldwide condition of NAFLD and the state of the probiotic market.

Gut Microbiome in the Progression of NAFLD, NASH and Cirrhosis, and Its Connection with Biotics: A Bibliometric Study Using Dimensions Scientific Research Database.

There is growing evidence that gut microbiota dysbiosis is linked to the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), from the initial stage of disease until the progressive stage of nonalcoholic steatohepatitis (NASH) and the final stage of cirrhosis. Conversely, probiotics, prebiotics, and synbiotics have shown promise in restoring dysbiosis and lowering clinical indicators of disease in a number of both preclinical and clinical studies. Additionally, postbiotics and parabiotics have recently garnered some attention. The purpose of this bibliometric analysis is to assess recent publishing trends concerning the role of the gut microbiome in the progression of NAFLD, NASH and cirrhosis and its connection with biotics. The free access version of the Dimensions scientific research database was used to find publications in this field from 2002 to 2022. VOSviewer and Dimensions' integrated tools were used to analyze current research trends. Research into the following topics is expected to emerge in this field: (1) evaluation of risk factors which are correlated with the progression of NAFLD, such as obesity and metabolic syndrome; (2) pathogenic mechanisms, such as liver inflammation through toll-like receptors activation, or alteration of short-chain fatty acids metabolisms, which contribute to NAFLD development and its progression in more severe forms, such as cirrhosis; (3) therapy for cirrhosis through dysbiosis reduction, and research on hepatic encephalopathy a common consequence of cirrhosis; (4) evaluation of diversity, and composition of gut microbiome under NAFLD, and as it varies under NASH and cirrhosis by rRNA gene sequencing, a tool which can also be used for the development of new probiotics and explore into the impact of biotics on the gut microbiome; (5) treatments to reduce dysbiosis with new probiotics, such as Akkermansia, or with fecal microbiome transplantation.

Gut-Liver Axis and Non-Alcoholic Fatty Liver Disease: A Vicious Circle of Dysfunctions Orchestrated by the Gut Microbiome.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent, multifactorial, and poorly understood liver disease with an increasing incidence worldwide. NAFLD is typically asymptomatic and coupled with other symptoms of metabolic syndrome. The prevalence of NAFLD is rising in tandem with the prevalence of obesity. In the Western hemisphere, NAFLD is one of the most prevalent causes of liver disease and liver transplantation. Recent research suggests that gut microbiome dysbiosis may play a significant role in the pathogenesis of NAFLD by dysregulating the gut-liver axis. The so-called "gut-liver axis" refers to the communication and feedback loop between the digestive system and the liver. Several pathological mechanisms characterized the alteration of the gut-liver axis, such as the impairment of the gut barrier and the increase of the intestinal permeability which result in endotoxemia and inflammation, and changes in bile acid profiles and metabolite levels produced by the gut microbiome. This review will explore the role of gut-liver axis disruption, mediated by gut microbiome dysbiosis, on NAFLD development.

Effects of Topical Gabapentin on Ocular Pain and Tear Secretion.

Neuropathic ocular pain is a frequent occurrence in medium to severe dry eye disease (DED). Only palliative treatments, such as lubricants and anti-inflammatory drugs, are available to alleviate patients' discomfort. Anesthetic drugs are not indicated, because they may interfere with the neural feedback between the cornea and the lacrimal gland, impairing tear production and lacrimation. Gabapentin (GBT) is a structural analog of gamma-amino butyric acid that has been used by systemic administration to provide pain relief in glaucomatous patients. We have already shown in a rabbit model system that its topic administration as eye drops has anti-inflammatory properties. We now present data on rabbits' eyes showing that indeed GBT given topically as eye drops has analgesic but not anesthetic effects. Therefore, opposite to an anesthetic drug such as oxybuprocaine, GBT does not decrease lacrimation, but-unexpectedly-even stimulates it, apparently through the upregulation of acetylcholine and norepinephrine, and by induction of aquaporin 5 (AQP5) expression in the lacrimal gland. Moreover, data obtained in vitro on a primary human corneal epithelial cell line also show direct induction of AQP5 by GBT. This suggests that corneal cells might also contribute to the lacrimal stimulation promoted by GBT and participate with lacrimal glands in the restoration of the tear film, thus reducing friction on the ocular surface, which is a known trigger of ocular pain. In conclusion, GBT is endowed with analgesic, anti-inflammatory and secretagogue properties, all useful to treat neuropathic pain of the ocular surface, especially in case of DED.

Dietary Supplementation of Antioxidant Compounds Prevents Light-Induced Retinal Damage in a Rat Model.

Light-induced retinal damage (LD) is characterized by the accumulation of reactive oxygen species leading to oxidative stress and photoreceptor cell death. The use of natural antioxidants has emerged as promising approach for the prevention of LD. Among them, lutein and cyanidin-3-glucoside (C3G) have been shown to be particularly effective due to their antioxidant and anti-inflammatory activity. However, less is known about the possible efficacy of combining them in a multicomponent mixture. In a rat model of LD, Western blot analysis, immunohistochemistry and electroretinography were used to demonstrate that lutein and C3G in combination or in a multicomponent mixture can prevent oxidative stress, inflammation, gliotic and apoptotic responses thus protecting photoreceptor cells from death with higher efficacy than each component alone. Combined efficacy on dysfunctional electroretinogram was also demonstrated by ameliorated rod and cone photoreceptor responses. These findings suggest the rationale to formulate multicomponent blends which may optimize the partnering compounds bioactivity and bioavailability.

Atropine Differentially Modulates ECM Production by Ocular Fibroblasts, and Its Ocular Surface Toxicity Is Blunted by Colostrum.

 Background: The etiology and the mechanism behind atropine treatment of progressive myopia are still poorly understood. Our study addressed the role of scleral and choroidal fibroblasts in myopia development and atropine function. METHODS: Fibroblasts treated in vitro with atropine or 7-methylxanthine were tested for ECM production by Western blotting. Corneal epithelial cells were treated with atropine in the presence or absence of colostrum or fucosyl-lactose, and cell survival was evaluated by the MTT metabolic test. RESULTS: Atropine and 7-methyl-xanthine stimulated collagen I and fibronectin production in scleral fibroblasts, while they inhibited their production in choroidal fibroblasts. Four days of treatment with atropine of corneal epithelial cells significantly decreased cell viability, which could be prevented by the presence of colostrum or fucosyl-lactose. CONCLUSIONS: Our results show that atropine may function in different ways in different eye districts, strengthening the scleral ECM and increasing permeability in the choroid. The finding that colostrum or fucosyl-lactose attenuate the corneal epithelial toxicity after long-term atropine treatment suggests the possibility that both compounds can efficiently blunt its toxicity in children subjected to chronic atropine treatment.

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.

TRAIL-related neurotoxicity implies interaction with the Wnt pathway in human neuronal cells in vitro.

Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is involved in amyloid beta dependent neurotoxicity via the extrinsic pathway. Recently, several genes modulating TRAIL cytotoxicity have been characterized, providing evidence for a role of wingless-type mouse mammary tumor virus integration site family (Wnt), Jun-N-terminal kinase and other pathways in increased cell susceptibility to the cytokine. We investigated whether neurotoxic effects of TRAIL could be due to modulation of the Wnt signaling pathway. Western blot analysis of Wnt in SH-SY5Y human neuroblastoma cells showed significantly decreased Wnt expression in cultures treated with TRAIL. Correspondingly, both phosphorylation of glycogen synthase kinase 3 beta and degradation of cytoplasmic beta-catenin were increased, as well as phosphorylation of the tau protein, bringing about the picture of neuronal damage. As a counterproof of the interaction of TRAIL with the Wnt pathway, the addition of the specific glycogen synthase kinase 3 beta inhibitor SB216763 resulted in rescue of a significant percent of cells from TRAIL-induced apoptosis. The rescue was total when the caspase 8 inhibitor z-IETD-FMK was added in combination with SB216763. Results show that, probably, in addition to triggering caspase signaling, TRAIL also interferes with the Wnt pathway, additionally concurring to neuronal damage. These data suggest that the Wnt pathway substantially contributes to the TRAIL-related neurotoxicity and indicate the TRAIL system as a candidate target for pharmacological treatment of Alzheimer's disease and related disorders.

The role of antioxidant supplement in immune system, neoplastic, and neurodegenerative disorders: a point of view for an assessment of the risk/benefit profile.

This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.

Experimental Evidence of the Healing Properties of Lactobionic Acid for Ocular Surface Disease.

PURPOSE: The aim of this study was to investigate the properties of lactobionic acid (LA) as a possible supplement in artificial tears in in vitro and in vivo experimental model systems. LA is a bionic derivative of a polyhydroxy acid, which consists of one galactose attached by an ether link to a gluconic acid. It is a molecule endowed with several properties that make it an ideal supplement in artificial tears: it is highly hygroscopic and a powerful antioxidant, it is an iron chelator and inhibits matrix metalloprotease activity; it favors wound healing (WH); and it inhibits bacterial growth. METHODS: Promotion of WH by LA, alone or in combination with hyaluronic acid (HA), was investigated in vitro on monolayers of rabbit corneal cells (Statens Seruminstitut) and in vivo after epithelium debridement of rabbit corneas. TGF-ß expression and MMP-9 activity in wounded corneas were detected in tears and cornea extracts by western blot or by Enzyme Linked ImmunoSorbent Assay (ELISA). Bacterial growth inhibition by LA was checked on Staphylococcus aureus isolates in liquid culture. RESULTS: LA, with or without HA, favors WH in vitro and in vivo. The WH assay on the rabbit cornea showed that 4% LA in association with 0.15% HA also resulted in a blunted increase of MMP-9 and TGF-ß in tears and corneal tissue. Finally, the presence of 4% LA resulted in slower growth of cultured bacterial isolates. CONCLUSIONS: Our findings support the hypothesis that LA could be a useful supplement to artificial tears to treat ocular surface dysfunction such as dry eye.

Protective effects of the sigma agonist Pre-084 in the rat retina.

AIM: With the rationale that amyloid beta (AB) is toxic to the retina, we here assessed the role of TRAIL, a mediator of AB toxicity and related signal transduction, in a rat model. We also attempted to demonstrate possible protective effects of sigma 1 receptor agonists in these processes. METHODS: AB and the sigma 1 receptor agonist Pre-084 were injected intravitreally in the anaesthetised rat. In additional experiments, the sigma 1 receptor antagonist BD1047 was administered to assess specificity of the effects of Pre-084. Western blot analysis was performed on retinas to evaluate the expression of TRAIL and TRAIL receptors in the retina, as well as of Bax and phosphorylated JNK following the different treatments. Lactic dehydrogenase (LDH) levels were measured as a cytotoxicity marker. RESULTS: All TRAIL receptors were expressed in rat retinas. Intravitreal injection of AB in rat eyes induced overexpression of TRAIL and the proapoptotic protein Bax, as well as phosphorylation of JNK. All these effects of AB were abrogated by pretreatment with the sigma(1) receptor agonist Pre-084. CONCLUSIONS: It is likely that TRAIL is a mediator of AB effects on the retina. In light of their specific inhibitory effects upon TRAIL expression, it is plausible to hypothesise that sigma(1) receptor agonists could represent potential pharmacological tools for restraining AB related retinal damage.

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.

Gabapentin Attenuates Ocular Inflammation: In vitro and In vivo Studies.

To investigate the effects of gabapentin, a structural analog of γ-amino butyric acid (GABA), on the inflammatory response of lipopolysaccharide (LPS)-stimulated rabbit corneal cells (SIRC) and on endotoxin-induced uveitis (EIU) in rabbits. We investigated the LPS-induced expression of several inflammatory mediators, such as TNF-α, IL-1ß, cPLA2, COX-2, and PGE2 in the SIRC cells with or without gabapentin treatment. Gabapentin treatment significantly (p < 0.05) attenuated cytokines production, cPLA2 activation, COX-2 expression, and PGE2 levels in SIRC. EIU was induced by an intraocular injection of 0.1 µg of LPS in albino rabbit eye. After 7 and 24 h from LPS injection clinical signs of ocular inflammation were examined by slit lamp with or without topical treatment of 0.5% gabapentin. Tears, aqueous, cornea, conjunctiva, and iris-ciliary body were collected and inflammatory biomarkers assessed. Topical treatment with gabapentin significantly (p < 0.05) reduced clinical signs and biomarkers of inflammation compared with the LPS group both at 7 and 24 h. In conclusion, the results generated in the present study suggest that ophthalmic formulation based on gabapentin may be useful in the treatment of inflammatory conditions associated to ocular pain such as uveitis, and that clinical studies to evaluate this possibility may be warranted.