Development of transferosomes for topical ocular drug delivery of curcumin.

BACKGROUND: Transferosomes (TFS) are ultra-deformable elastic bilayer vesicles that have previously been used to enhance gradient driven penetration through the skin. This study aimed to evaluate the potential of TFS for topical ocular drug delivery and to compare their penetration enhancing properties in different ocular tissues. METHODS: Curcumin-loaded TFS were prepared using Tween 80 as the edge activator. Drug release and precorneal retention of the TFS were evaluated in vitro, while their ocular biocompatibility and bioavailability were evaluated ex vivo using a curcumin solution in medium chain triglycerides as the oily control. RESULTS: The TFS had a narrow size distribution with a particle size less than 150 nm and an entrapment efficiency greater than 99.96 %. Burst release from the TFS was minimal and the formulation showed good corneal biocompatibility. Moreover, enhanced corneal and conjunctival drug penetration with significantly greater and deeper drug delivery was observed with TFS in all ocular tissues. CONCLUSION: TFS offer a promising platform for ocular delivery of hydrophobic drugs. This study, for the first time, elucidates the effect of tissue morphology and osmotic gradients on drug penetration in different ocular tissues.

Utilizing an Ex Vivo Skin Penetration Analysis Model for Predicting Ocular Drug Penetration: A Feasibility Study with Curcumin Formulations.

Objective: This study aimed to investigate the feasibility of using the digital image processing technique, developed to semi-quantitatively study dermal penetration, to study corneal penetration in an ex vivo porcine eye model. Here, we investigated various formulation strategies intended to enhance dermal and corneal bioavailability of the model hydrophobic drug, curcumin. METHODS: Several formulation principles were explored, including oily solutions, oily suspensions, aqueous nanosuspension, micelles, liposomes and cyclodextrins. The dermal penetration efficacy was tested using an ex vivo porcine ear model previously developed at Philipps-Universität Marburg with subsequent digital image processing. This image analysis method was further applied to study corneal penetration using an ex vivo porcine whole-eye model. RESULTS: For dermal penetration, oily solutions, oily suspensions and nanosuspensions exhibited the least penetration, whereas liposomes and cyclodextrins showed enhanced penetration. Corneal curcumin penetration correlated with dermal penetration, with curcumin loaded into cyclodextrins penetrating the deepest. CONCLUSIONS: Overall, our study suggests that the image analysis method previously developed for ex vivo skin penetration can easily be repurposed to study corneal penetration of hydrophobic drugs.

Development and validation of a stability-indicating HPLC method for assay of tonabersat in pharmaceutical formulations.

A stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed to assay tonabersat and assess its stability in pharmaceutical formulations. Chromatographic separation was achieved using a Kinetex® C18 column (2.6 µm, 150 x 3 mm, 100 Å) at 50 °C, with a 20 µL injection volume. A linear gradient of acetonitrile in water (5 - 33.5 %) was applied for 1 min, followed by a gradual increase to 100 % over 26 min at a flow rate of 0.5 mL/min. Tonabersat and its degradation products were detected at 275 nm and 210 nm, respectively. The optimized method was used to evaluate the stability of tonabersat in lipid-based pharmaceutical formulations at 5 ± 3 °C, 25 ± 2°C/60 ± 5 % RH, and 40 ± 2 °C/75 ± 5 % RH over 3 months. The method was validated as per ICH guidelines and demonstrated linearity in the range of 5 - 200 µg/mL (R2 = 0.99994) with good accuracy (98.25 - 101.58 % recovery) and precision (% RSD < 2.5 %). The limits of detection and quantitation were 0.8 µg/mL and 5 µg/mL, respectively. Forced degradation studies showed significant degradation on exposure to alkaline (90.33 ± 0.80 %), acidic (70.60 ± 1.57 %), and oxidative stress (33.95 ± 0.69 %) at 70 °C, but no degradation was observed on exposure to thermal or photolytic stress. No chemical degradation was observed in either formulation on storage. Thus, the method was sensitive, specific, and suitable for stability testing of tonabersat in pharmaceutical formulations.

Inflammation in Dry Eye Disease-Pathogenesis, Preclinical Animal Models, and Treatments.

Dry eye disease (DED) is a rapidly growing ocular surface disease with a significant socioeconomic impact that affects the patients' visual function and, thus, their quality of life. It is distinguished by a loss of tear film homeostasis, leading to tear film instability, hyperosmolarity, ocular surface inflammation, and neurosensory abnormalities, with all of these playing etiological roles in the propagation of the vicious DED circle. While current treatments primarily focus on reducing tear film instability and hyperosmolarity, increasingly more attention is being placed on tackling the underlying inflammation that propagates and potentiates these factors. As such, preclinical models are crucial to further elucidate the DED pathophysiology and develop novel therapeutic strategies. This review outlines the role of inflammation in DED, highlighting related signs and diagnostic tools before focusing on relevant preclinical animal models and potential therapeutic strategies to tackle DED-associated inflammation.

Mechanism of Ocular Penetration of Lipophilic Drugs from Lipophilic Vehicles.

Since eyedrops have conventionally been formulated in aqueous vehicles, ocular pharmacokinetic studies are generally performed using aqueous buffers to identify physicochemical properties of the drug and the vehicles that influence drug absorption. In recent years, biocompatible lipophilic vehicles are increasingly finding application in ocular drug delivery; however, the mechanism of drug penetration from these non-aqueous vehicles is poorly understood. This study aims to compare ocular penetration of the model lipophilic drug curcumin when incorporated into lipophilic vehicles. To elucidate whether intrinsic solubility in the lipophilic vehicle influences ocular penetration, a curcumin solution and suspension were prepared in medium chain triglycerides (MCT) and squalane, respectively. Ocular penetration and distribution of curcumin from both vehicles was compared and evaluated qualitatively and quantitatively ex vivo. Significantly greater and faster penetration was observed from the squalane suspension than from the MCT solution in all ocular tissues. Our results suggest that the ability of lipophilic drugs to partition out of lipophilic vehicles and into cell membranes, rather than their intrinsic solubility in the lipophilic vehicle, determines the rate and extent of their ocular penetration.

Progress in Ocular Drug Delivery: Challenges and Constraints.

The eye has several dynamic and static barriers in place to limit the entry of foreign substances including therapeutics. As such, efficient drug delivery, especially to posterior segment tissues, has been challenging. This chapter describes the anatomical and physiological challenges associated with ocular drug delivery before discussing constraints with regard to formulation parameters. Finally, it gives an overview of advanced drug delivery technologies with a specific focus on recently marketed and late-stage clinical trial products.

NLRP3 Inflammasome as a Potential Therapeutic Target in Dry Eye Disease.

Dry eye disease (DED) is a multifactorial ocular surface disorder arising from numerous interrelated underlying pathologies that trigger a self-perpetuating cycle of instability, hyperosmolarity, and ocular surface damage. Associated ocular discomfort and visual disturbance contribute negatively to quality of life. Ocular surface inflammation has been increasingly recognised as playing a key role in the pathophysiology of chronic DED. Current readily available anti-inflammatory agents successfully relieve symptoms, but often without addressing the underlying pathophysiological mechanism. The NOD-like receptor protein-3 (NLRP3) inflammasome pathway has recently been implicated as a key driver of ocular surface inflammation, as reported in pre-clinical and clinical studies of DED. This review discusses the intimate relationship between DED and inflammation, highlights the involvement of the inflammasome in the development of DED, describes existing anti-inflammatory therapies and their limitations, and evaluates the potential of the inflammasome in the context of the existing anti-inflammatory therapeutic landscape as a therapeutic target for effective treatment of the disease.

Comprehensive Grading System for Experimental Autoimmune Uveitis in Mice.

Experimental autoimmune uveitis (EAU) is the most commonly used animal model to study the progression of chronic uveitis and to test various therapies to treat the disease. However, to accurately evaluate the effectiveness of such treatments, a grading system that combines the latest imaging techniques with definitive quantitative grading thresholds is required. This study aimed to develop a comprehensive grading system that objectively evaluates EAU progression in C57BL/6J mice. EAU was induced following immunisation with interphotoreceptor retinoid-binding protein (IRBP) and pertussis toxin. Weekly fundus and optical coherence tomography (OCT) images were acquired over 12 weeks using a Micron IV imaging system. Each mouse was graded (between 0 to 4) based on changes seen on both the fundus (optic disc, retinal blood vessels and retinal tissue) and OCT (vitreous and retinal layers) images. A total EAU response (with a maximum score of 48) was calculated for each mouse based on the sum of the individual scores each week. Analysis of the clinical scores depicted a gradual increase in inflammatory signs including optic disc and vascular swelling, leukocyte infiltration in the vitreous, lesions in the retina and formation of granulomas and hyper-reflective foci in the retinal layers in EAU mice, with most signs reaching a plateau towards the end of the study period. Development of these signs into sight-threatening complications such as optic disc atrophy, structural damage to the retina and subretinal oedema were noted in 80-90% of mice suggesting consistent disease induction. Overall, a comprehensive and objective grading system encompassing all pathologies occurring in EAU mice was developed to enhance the preclinical evaluation of novel uveitis treatments.

Non-aqueous formulations in topical ocular drug delivery - A paradigm shift?

Topical eyedrop application is the preferred route for drug delivery to anterior segment tissues; however, the challenge of overcoming the eye's anatomical and physiological barriers while minimising tissue toxicity has restricted developments in this field. Aqueous vehicles have traditionally been used, which typically require several additives and preservatives to achieve physiologically compatible and sterile eyedrops, elevating their toxicity potential. Non-aqueous vehicles have been suggested as efficient alternatives for topical drug delivery as they can address many of the limitations associated with conventional aqueous eyedrops. However, despite their obvious advantages, non-aqueous eyedrops remain poorly researched and few non-aqueous formulations are currently available in the market. This review challenges the conventional hypothesis that aqueous solubility is a prerequisite to ocular drug absorption and establishes a rationale for using non-aqueous vehicles for ocular drug delivery. Recent advances in the field have been detailed and future research prospects have been explored, pointing towards a paradigm shift in eyedrop formulation in the near future.

Preclinical characterization of water-free cyclosporine eye drops - Factors impacting ocular penetration ex vivo and in vivo.

Although the efficacy of Cyclosporine A (CsA) in the management of ocular inflammation is well-demonstrated, ocular delivery remains challenging due to its hydrophobic nature. The semifluorinated alkane, perfluorobutylpentane (F4H5) has previously been suggested as an efficient vehicle for preparation of CsA eyedrops. Here we evaluated the influence of drop volume and the formulation aid, ethanol (EtOH), on ocular penetration of CsA and compared it to that of the commercial eyedrop, Ikervis, ex vivo and in vivo. Moreover, conjunctival and corneal tolerability after EtOH addition were evaluated ex vivo. The F4H5/EtOH vehicle was well tolerated and resulted in better corneal CsA penetration (AUC(0-4h): 63,008 ± 3,946 ng.h.g-1) than Ikervis (AUC(0-4h): 10,328 ± 1,462 ng.h.g-1) or F4H5 alone (AUC(0-4h): 50,734 ± 3,472 ng.h.g-1) ex vivo. Interestingly, in vivo the CsA concentration in cornea, conjunctiva and lacrimal glands observed after administration of the F4H5 formulation (AUC(0.133-24h): 7,741 ± 1,334 ng.h.g-1, 1,313 ± 291 ng.h.g-1, 48.2 ± 26.3 ng.h.g-1) and F4H5/EtOH, both at a reduced dose of 11 µl (AUC(0.133-24h): 9,552 ± 1,738 ng.h.g-1, 1,679 ± 285 ng.h.g-1, 50.3 ± 21.1 ng.h.g-1) was similar or even greater than that observed on administration of 50 µl Ikervis (AUC(0.133-24h): 9,943 ± 1,413 ng.h.g-1, 2,069 ± 263 ng.h.g-1, 30.6 ± 18.4 ng.h.g-1). Thus, F4H5-based eyedrops were shown to deliver CsA more efficiently to anterior ocular tissues at a reduced dose in comparison to Ikervis, reducing dose wastage and minimizing any potential systemic side effects.

Physicochemical properties and micro-interaction between micro-nanoparticles and anterior corneal multilayer biological interface film for improving drug delivery efficacy: the transformation of tear film turnover mode.

Recently, various novel drug delivery systems have been developed to overcome ocular barriers in order to improve drug efficacy. We have previously reported that montmorillonite (MT) microspheres (MPs) and solid lipid nanoparticles (SLNs) loaded with the anti-glaucoma drug betaxolol hydrochloride (BHC) exhibited sustained drug release and thus intraocular pressure (IOP) lowering effects. Here, we investigated the effect of physicochemical particle parameters on the micro-interactions with tear film mucins and corneal epithelial cells. Results showed that the MT-BHC SLNs and MT-BHC MPs eye drops significantly prolonged the precorneal retention time due to their higher viscosity and lower surface tension and contact angle compared with the BHC solution, with MT-BHC MPs exhibiting the longest retention due to their stronger hydrophobic surface. The cumulative release of MT-BHC SLNs and MT-BHC MPs was up to 87.78% and 80.43% after 12 h, respectively. Tear elimination pharmacokinetics study further confirmed that the prolonged precorneal retention time of the formulations was due to the micro-interaction between the positively charged formulations and the negatively charged tear film mucins. Moreover, the area under the IOP reduction curve (AUC) of MT-BHC SLNs and MT-BHC MPs was 1.4 and 2.5 times that of the BHC solution. Accordingly, the MT-BHC MPs also exhibit the most consistent and long-lasting IOP-lowering effect. Ocular irritation experiments showed no significant toxicity of either. Taken together, MT MPs may have the potential for more effective glaucoma treatment.

Orally Delivered Connexin43 Hemichannel Blocker, Tonabersat, Inhibits Vascular Breakdown and Inflammasome Activation in a Mouse Model of Diabetic Retinopathy.

Diabetic retinopathy (DR), a microvascular complication of diabetes, is associated with pronounced inflammation arising from the activation of a nucleotide-binding and oligomerization domain-like receptor (NLR) protein 3 (NLRP3) inflammasome. Cell culture models have shown that a connexin43 hemichannel blocker can prevent inflammasome activation in DR. The aim of this study was to evaluate the ocular safety and efficacy of tonabersat, an orally bioavailable connexin43 hemichannel blocker, to protect against DR signs in an inflammatory non-obese diabetic (NOD) DR mouse model. For retina safety studies, tonabersat was applied to retinal pigment epithelial (ARPE-19) cells or given orally to control NOD mice in the absence of any other stimuli. For efficacy studies, either tonabersat or a vehicle was given orally to the inflammatory NOD mouse model two hours before an intravitreal injection of pro-inflammatory cytokines, interleukin-1 beta, and tumour necrosis factor-alpha. Fundus and optical coherence tomography images were acquired at the baseline as well as at 2- and 7-day timepoints to assess microvascular abnormalities and sub-retinal fluid accumulation. Retinal inflammation and inflammasome activation were also assessed using immunohistochemistry. Tonabersat did not have any effect on ARPE-19 cells or control NOD mouse retinas in the absence of other stimuli. However, the tonabersat treatment in the inflammatory NOD mice significantly reduced macrovascular abnormalities, hyperreflective foci, sub-retinal fluid accumulation, vascular leak, inflammation, and inflammasome activation. These findings suggest that tonabersat may be a safe and effective treatment for DR.

Extracellular Vesicles as Biomarkers and Therapeutics for Inflammatory Eye Diseases.

Extracellular vesicles (EVs) are a group of cell-derived membrane vesicles of varying sizes that can be secreted by most cells. Depending on the type of cell they are derived from, EVs may contain a variety of cargo including proteins, lipids, miRNA, and DNA. Functionally, EVs play important roles in physiological and pathological processes through intercellular communication. While there has already been significant literature on the involvement of EVs in neurological and cardiovascular disease as well as cancer, recent evidence suggests that EVs may also play a role in mediating inflammatory eye diseases. This paper summarizes current advancements in ocular EV research as well as new ways by which EVs may be utilized as novel biomarkers of or therapeutics for inflammatory eye diseases.

Critical Evaluation of Multifunctional Betaxolol Hydrochloride Nanoformulations for Effective Sustained Intraocular Pressure Reduction.

Introduction: Glaucoma is a chronic disease that requires long-term adherence to treatment. Topical application of conventional eye drops results in substantial drug loss due to rapid tear turnover, with poor drug bioavailability being a major challenge for efficient glaucoma treatment. We aimed to prepare the anti-glaucoma drug betaxolol hydrochloride (BH) as a novel nano-delivery system that prolonged the retention time at the ocular surface and improved bioavailability. Methods: We constructed multifunctional nanoparticles (MMt-BH-HA/CS-ED NPs) by ion cross-linking-solvent evaporation method. The particle size, zeta potential, encapsulation efficiency and drug loading of MMt-BH-HA/CS-ED NPs were physicochemically characterized. The structure of the preparations was characterized by microscopic techniques of SEM, TEM, XPS, XRD, FTIR and TGA, and evaluated for their in vitro release performance as well as adhesion properties. Its safety was investigated using irritation assays of hemolysis experiment, Draize test and histopathology examination. Precorneal retention was examined by in vivo fluorescence tracer method and pharmacokinetics in tear fluid was studied. A model of high IOP successfully induced by injection of compound carbomer solution was used to assess the IOP-lowering efficacy of the formulation, and it was proposed that micro-interactions between the formulation and the tear film would be used to analyze the behavior at the ocular surface. Results: The positively charged MMt-BH-HA/CS-ED NPs were successfully prepared with good two-step release properties, higher viscosity, and slower pre-corneal diffusion rate along with longer precorneal retention time compared to BH solution. The micro-interactions between nanoparticles and tear film converted the drug clearance from being controlled by fast aqueous layer turnover to slow mucin layer turnover, resulting in higher drug concentration on the ocular surface, providing more durable and stable IOP-lowering efficacy. Conclusion: The novel multifunctional MMt-BH-HA/CS-ED NPs can effectively reduce IOP and are suitable for the treatment of chronic disease glaucoma.

Characterization of NLRP3 Inflammasome Activation in the Onset of Diabetic Retinopathy.

The aim of this study was to characterize the role of nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome activation in the onset of diabetic retinopathy (DR) using retina and vitreous from donors without diabetes mellitus (CTL), with diabetes mellitus alone (DM), and with DR. Retinal expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1), the key markers of retinal inflammation, connexin43 (Cx43) which is involved in upstream inflammasome regulation, as well as NLRP3 and cleaved caspase-1, the main markers of inflammasome activation, were evaluated using immunohistochemistry and Western blotting. Vitreous interleukin (IL)-1ß and IL-18, biomarkers of the activated inflammasome, were measured using a Luminex multiplex assay. Results showed a significant increase in the number and size of Iba-1+ cells and NLRP3 expression in DM, while a significant increase in GFAP, Cx43, cleaved caspase-1 and vitreous IL-18, as well as a further increase in Iba-1 and NLRP3 was found in DR. This suggests that the inflammasome is already primed in DM before its activation in DR. Furthermore, IL-18 may act as the major effector of inflammasome activation in DR while nuclear translocation of cleaved caspase-1 may play a role in gene transcription contributing to DR onset.

Preparation and Characterisation of a Cyclodextrin-Complexed Manuka Honey Microemulsion for Eyelid Application.

Honey has been widely purported as a natural remedy due to its antimicrobial and anti-inflammatory effects. In recent years, several studies have suggested that the considerably high methylglyoxal (MGO) concentration in Manuka honey (MH) makes it particularly effective to manage bacterial overload, such as that observed in blepharitis. However, the poor solubility, high viscosity, and osmolarity of aqueous honey solutions, especially at the high MGO concentrations studied in the literature, render the formulation of an acceptable dosage form for topical application to the eyelids challenging. Here, the antibacterial properties of raw MH and alpha-cyclodextrin (α-CD)-complexed MH were evaluated at relatively low MGO concentrations, and a liquid crystalline-forming microemulsion containing α-CD-complexed MH was formulated. After determining pH and osmolarity, ocular tolerability was assessed using human primary corneal epithelial cells and chorioallantoic membranes, while the antibacterial efficacy was further evaluated in vitro. The α-CD-MH complex had significantly greater antibacterial activity against Staphylococcus aureus than either constituent alone, which was evident even when formulated as a microemulsion. Moreover, the final formulation had a physiologically acceptable pH and osmolarity for eyelid application and was well-tolerated when diluted 1:10 with artificial tear fluid, as expected to be the case after accidental exposure to the ocular surface in the clinical setting. Thus, a safe and efficient MH dosage form was developed for topical application to the eyelids, which can potentially be used to support optimal eyelid health in the management of blepharitis.

Preclinical confirmation of UVC efficacy in treating infectious keratitis.

PURPOSE: Preclinical evaluation of the therapeutic potential of antimicrobial 265 nm UVC for infectious keratitis. METHODS: Four experiments explored UVC: 1) impact on bacterial and fungal lawns on agar, in individual or mixed culture, 2) bacterial inactivation dose in an in vitro deep corneal infection model, 3) dose validation in an ex vivo porcine keratitis model and 4) efficacy in a masked, randomised, controlled murine keratitis trial using bioluminescent Pseudomonas aeruginosa. RESULTS: Minimum effective UVC exposures ranged between 2 s and 5 s for lawn bacteria and fungi in individual or mixed culture. Significant P. aeruginosa growth inhibition in the in vitro infection model was achieved with 15 s UVC, that resulted in a >3.5 log10 reduction of bacteria in a subsequent ex vivo keratitis model (p < 0.05). Bioluminescence fell below baseline levels in all treated animals, within 8 h of treatment (p < 0.05), in the in vivo study. Re-epithelialisation with corneal clarity occurred within 24 h in 75% of UVC-treated cases, with no relapse at 48 h. On plating, bacteria were recovered only from untreated controls. CONCLUSIONS: UVC inhibited all tested bacteria and fungi, including mixed culture and strains linked to antibiotic resistance, in vitro, with exposures of ≤ 5 s. In vitro and ex vivo testing confirmed therapeutic potential of 15 s UVC. In vivo, 15 s UVC administered in two doses, 4 h apart, proved effective in treating murine bacterial keratitis.

Correlation between the progression of diabetic retinopathy and inflammasome biomarkers in vitreous and serum - a systematic review.

Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway has been implicated in Diabetic retinopathy (DR) pathogenesis, but its impact on DR development and progression remains unclear. Therefore, the primary aim of this systematic literature review was to determine the role of the inflammasome in DR development. Furthermore, the secondary aim was to determine whether systemic inflammasome activity can be used to predict DR progression. Studies measuring vitreous and/or serum inflammasome biomarkers in DR patients with Type 2 Diabetes Mellitus (T2DM) were searched systematically using online databases EMBASE, PubMed and Web of Science with the last search conducted on 29th of September 2021. The risk of bias was assessed using the Newcastle Ottawa Scale and 20 studies were eligible for narrative analysis. Limitations included the heterogeneity in detection assays used, the small and uneven sample size, a lack of vitreous data in earlier disease stages, and not accounting for patients with other systemic co-morbidities. Analysis showed that inflammasome biomarkers IL-1ß and IL-18 increased significantly from non-proliferative DR to proliferative DR in both vitreous and serum, suggesting the inflammasome pathway is activated as DR progresses and that serum inflammasome levels could be explored as potential biomarkers for DR progression.

Blocking connexin43 hemichannels prevents TGF-ß2 upregulation and epithelial-mesenchymal transition in retinal pigment epithelial cells.

Epithelial-mesenchymal transition (EMT) occurs when polarised epithelial cells change to a mesenchymal phenotype. EMT plays a role in several chronic conditions, including ocular diseases with retinal pigment epithelium (RPE) EMT associated with retinal diseases such as diabetic retinopathy (DR). Here, EMT results in breakdown of the blood-retinal barrier (BRB) leading to sub-retinal fluid deposition and retinal detachment. Previous studies have shown that blocking connexin43 (Cx43) hemichannels can protect against RPE BRB breakdown, but the underlying mechanism is unknown. To determine whether open Cx43 hemichannels may enable EMT of RPE cells and thus result in BRB breakdown, ARPE-19 cells were either challenged with high glucose plus the inflammatory cytokines IL-1ß and TNF-α (HG + Cyt) to simulate DR or treated with the Cx43 hemichannel blocker tonabersat alongside the HG + Cyt challenge. HG + Cyt induced a morphological change in RPE cells to a fibroblastic phenotype with a corresponding decrease in epithelial zonular occludens-1 and an increase in the fibroblastic marker α-SMA. The HG + Cyt challenge also induced loss of transepithelial electrical resistance while increasing dye passage between RPE cells. All of these changes were significantly reduced with tonabersat treatment, which also prevented HG + Cyt-induced transforming growth factor-ß2 (TGF-ß2) release. In conclusion, Cx43 hemichannel block with tonabersat attenuated both TGF-ß2 release and RPE EMT under disease-mimicking conditions, offering the potential to ameliorate the progression of EMT-associated retinal diseases.

Blocking the inflammasome: A novel approach to treat uveitis.

Uveitis is a complex ocular inflammatory disease often accompanied by bacterial or viral infections (infectious uveitis) or underlying autoimmune diseases (non-infectious uveitis). Treatment of the underlying infection along with corticosteroid-mediated suppression of acute inflammation usually resolves infectious uveitis. However, to develop more effective therapies for non-infectious uveitis and to better address acute inflammation in infectious disease, an improved understanding of the underlying inflammatory pathways is needed. In this review, we discuss the disease aetiology, preclinical in vitro and in vivo uveitis models, the role of inflammatory pathways, as well as current and future therapies. In particular, we highlight the involvement of the inflammasome in the development of non-infectious uveitis and how it could be a future target for effective treatment of the disease.