Unveiling the P2X7 receptor: Exploring its mechanisms, pathogenic role in ocular diseases, and emerging therapeutic potential.

P2X purinoceptor 7 receptor (P2X7R) is an ATP-gated ion channel that, upon activation by ATP, triggers the release of inflammatory mediators and induces apoptosis in cells. This channel plays a crucial role in the onset and progression of various diseases. Recently, there has been a growing body of research focused on the function of P2X7R receptors in ophthalmic conditions, particularly concerning retinal diseases such as age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. This article is to provide a comprehensive review of the advancements in the study of P2X7R and its association with retinal diseases, elucidating its role in these conditions and identifying potential avenues for future research. Electronic databases, including PubMed, Web of Science, and Wan fang Data were searched for relevant literature. The following keywords were used: "P2X7R", Age-related macular degeneration", "Diabetic retinopathy", "Retinitis pigmentosa". Both preclinical and clinical studies were included to provide a holistic understanding of P2X7R's role in retinal pathology. P2X7R activation exacerbates retinal diseases by promoting inflammation and apoptosis. However, its role in disease progression and homeostasis complicates therapeutic targeting, highlighting the need for selective inhibitors and further research into its context-dependent functions. P2X7R plays a critical role in the pathogenesis of retinal diseases. At the same time, preclinical studies suggest that P2X7R inhibition holds promise as a therapeutic strategy. Future research should focus on developing selective P2X7R inhibitors, elucidating the receptor's role in different disease stages, and identifying biomarkers to guide personalized treatment. Addressing these challenges will be essential for translating P2X7R-targeted therapies into clinical practice and improving outcomes for patients with retinal diseases.

Diabetes mellitus is a complex metabolic disease that has become a global epidemic with more than 285 million cases worldwide. Major medical advances over the past decades have substantially improved its management, extending patients' survival. The latter is accompanied by an increased risk of developing chronic macro- and microvascular complications. Amongst them, diabetic retinopathy (DR) is the most common and frightening. Furthermore, during the past two decades, it has become the leading cause of visual loss. Irrespective of the type of diabetes, DR follows a well-known clinical and temporal course characterized by pericytes and neuronal cell loss, formation of acellular-occluded capillaries, occasional microaneurysms, increased leucostasis and thickening of the vascular basement membrane. These alterations progressively affect the integrity of retinal microvessels, leading to the breakdown of the blood-retinal barrier, widespread haemorrhage and neovascularization. Finally, tractional retinal detachment occurs leading to blindness. Nowadays, there is growing evidence that local inflammation and oxidative stress play pivotal roles in the pathogenesis of DR. Both processes have been associated with pericytes and neuronal degeneration observed early during DR progression. They may also be linked to sustained retinal vasculature damage that results in abnormal neovascularization. Currently, DR therapeutic options depend on highly invasive surgical procedures performed only at advanced stages of the disease, and which have proved to be ineffective to restore visual acuity. Therefore, the availability of less invasive and more effective strategies aimed to prevent or delay the onset of DR is highly desirable. Multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs), are promising healing agents as they contribute to tissue regeneration by pleiotropic mechanisms, with no evidence of significant adverse events. Here, we revise the pathophysiology of DR to identify therapeutic targets for donor MSCs. Also, we discuss whether an MSC-based therapy could prevent or delay the onset of DR.

Microperimetry is a procedure to assess retinal sensitivity while fundus is examined directly. It is a psychophysical method which is rapid, safe and non-invasive. It combines analysis of function and morphology and has an eye tracking system that can improve the fixation stability of patient with eccentric fixation and fixation instable. Microperimetry is supplement to visual function, perimetry, and other visual function parameters. As deepening of research, its clinical application value in ocular fundus diseases including age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, Stargardt's disease, macular hole, rhegmatogenous retinal detachment and central serous chorioretinopathy needs to be further explored. Key words: Visual fields; Macular degeneration; Diabetic retinopathy; Central serous chorioretinopathy; Review

ABSTRACTBackground: The complement system has been implicated in the pathogenesis of age-related macular degeneration (AMD) and the CFH Y402H polymorphism has been suggested as a major risk factor for AMD. Recent evidences supported the role of inflammation in the pathogenesis of some retinal dystrophies. Aim of this study was to evaluate the prevalence of CFHY402H polymorphism in a group of Italian patients affected by atrophic AMD, Stargardt disease (STGD), or retinitis pigmentosa(RP).Materials and Methods: Our case–control association study included 116 patients with atrophic AMD, 77 with RP, 86 with STGD, and 100 healthy controls. All the patients were evaluated by a standard ophthalmologic examination and OCT. ERG was performed on STGD and RP patients. All the subjects underwent a blood drawing for genetic testing and the CFHY402H polymorphism was genotyped with the TaqMan real-time polymerase chain reaction single nucleotide polymorphism assay.Results: The prevalence of the risk genotype C/C was higher in the AMD group than in controls (p < 0.001). The risk allele C was more frequent in the AMD group than in controls (p < 0.001). The prevalence of the risk genotype was higher in the RP patients than in controls (p < 0.001) and similarly the risk allele C was more frequent in the RP group (p = 0.008). The CFHY402H genotype distribution was not different between patients with STGD and the controls, for the biallelic (p = 0.531) and for the monoallelic (p = 0.318) evaluation.Conclusions: In our series of Italian patients, the CFHY402H genotype is associated with atrophic AMD and RP, but not with STGD. This result may support the hypothesis of a complement system dysregulation in the pathogenesis of AMD and RP

Gene therapy for ocular disease.

Age-related macular degeneration (AMD) is a chronic and progressive inflammatory disease of the retina characterized by photoceptor loss and significant central visual impairment due to either choroidal neovascularization or geographic atrophy. The pathophysiology of AMD is complex and multifactorial, driven by a combination of modifiable and non-modifiable risk factors, molecular mechanisms, and cellular processes that contribute to overall disease onset, severity, and progression. Unfortunately, due to the structural, cellular, and pathophysiologic complexity, therapeutic discovery is challenging. While purinergic signaling has been investigated for its role in the development and treatment of ocular pathologies including AMD, the potential crosstalk between known contributors to AMD, such as the complement cascade and inflammasome activation, and other biological systems, such as purinergic signaling, have not been fully characterized. In this review, we explore the interactions between purinergic signaling, ATP release, and known contributors to AMD pathogenesis including complement dysregulation and inflammasome activation. We begin by identifying what is known about purinergic receptors in cell populations of the outer retina and potential sources of extracellular ATP required to trigger purinergic receptor activation. Next, we examine evidence in the literature that the purinergic system accelerates AMD pathogenesis leading to apoptotic and pyroptotic cell death in retinal cells. To fully understand the potential role that purinergic signaling plays in AMD, more research is needed surrounding the expression, distribution, functions, and interactions of purinergic receptors within cells of the outer retina as well as potential crosstalk with other systems. By determining how these processes are affected in the context of purinergic signaling, it will improve our understanding of the mechanisms that drive AMD pathogenesis which is critical in developing treatment strategies that prevent or slow progression of the disease.

Purinergic signaling in retinal degeneration and regeneration

Intravitreal triamcinolone acetonide (IVTA) has increasingly been applied as treatment for various intraocular neovascular and oedematous diseases. Comparing the various diseases with respect to effect and side-effects of the treatment, the best response in terms of gain in visual acuity (VA) has been achieved for intraretinal oedematous diseases such as diffuse diabetic macular oedema, branch retinal vein occlusion, central retinal vein occlusion and pseudophakic cystoid macular oedema. In eyes with various types of non-infectious uveitis, including acute or chronic sympathetic ophthalmia and Adamantiadis-Behcet's disease, VA increased and the degree of intraocular inflammation decreased. Some studies have suggested that intravitreal triamcinolone may be useful as angiostatic therapy in eyes with iris neovascularization and proliferative ischaemic retinopathies. Intravitreal triamcinolone may possibly be helpful as adjunct therapy for exudative age-related macular degeneration (AMD), particularly in combination with photodynamic therapy. In eyes with chronic, therapy-resistant ocular hypotony, intravitreal triamcinolone can induce an increase in intraocular pressure (IOP) and may stabilize the eye. The complications of intravitreal triamcinolone therapy include: secondary ocular hypertension in about 40% of the eyes injected; medically uncontrollable high IOP leading to antiglaucomatous surgery in about 1-2% of the eyes; posterior subcapsular cataract and nuclear cataract leading to cataract surgery in about 15-20% of elderly patients within 1 year of injection; postoperative infectious endophthalmitis occurring at a rate of about one per 1000; non-infectious endophthalmitis, perhaps due to a reaction to the solvent agent, and pseudo-endophthalmitis with triamcinolone acetonide crystals appearing in the anterior chamber. Intravitreal triamcinolone injection can be combined with other intraocular surgeries, including cataract surgery, particularly in eyes with iris neovascularization. Cataract surgery performed some months after the injection does not show a markedly elevated complication rate. The injection may be repeated if the resultant benefits decrease after the initial IVTA injection. In non-vitrectomized eyes, the duration of the effect and side-effects of a single intravitreal injection of triamcinolone is about 6-9 months for a dosage of about 20 mg, and about 2-4 months for a dosage of 4 mg. So far, it has remained unclear whether the solvent agent should be removed, and if so, how.

Extracellular ATP and its ultimate degradation product adenosine are potent extracellular signaling molecules that elicit a variety of pathophysiological pathways in retina through the activation of P2 and P1 purinoceptors, respectively. Excessive build-up of extracellular ATP accelerates pathologic responses in retinal diseases, whereas accumulation of adenosine protects retinal cells against degeneration or inflammation. This mini-review focuses on the roles of ATP and adenosine in three types of blinding diseases including age-related macular degeneration (AMD), glaucoma, and diabetic retinopathy (DR). Several agonists and antagonists of ATP receptors and adenosine receptors (ARs) have been developed for the potential treatment of glaucoma, DR and AMD: antagonists of P2X7 receptor (P2X7R) (BBG, MRS2540) prevent ATP-induced neuronal apoptosis in glaucoma, DR, and AMD; A1 receptor (A1R) agonists (INO-8875) lower intraocular pressure in glaucoma; A2A receptor (A2AR) agonists (CGS21680) or antagonists (SCH58261, ZM241385) reduce neuroinflammation in glaucoma, DR, and AMD; A3 receptor (A3R) agonists (2-Cl-lB-MECA, MRS3558) protect retinal ganglion cells (RGCs) from apoptosis in glaucoma.

Cells release ATP in response to physiologic stimuli. Extracellular ATP regulates a broad range of important cellular functions by activation of the purinergic receptors in the plasma membrane. The purpose of these studies was to assess the role of vesicular exocytosis in cellular ATP release. FM1-43 fluorescence was used to measure exocytosis and bioluminescence to measure ATP release in HTC rat hepatoma and Mz-Cha-1 human cholangiocarcinoma cells. Exposure to a Cl(-) channel inhibitor 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) (50-300 microM) stimulated a 5-100-fold increase in extracellular ATP levels within minutes of the exposure. This rapid response was not a result of changes in cell viability or Cl(-) channel activity. NPPB also potently stimulated ATP release in HEK293 cells and HEK293 cells expressing a rat P2X7 receptor indicating that P2X7 receptors are not involved in stimulation of ATP release by NPPB. In all cells studied, NPPB rapidly stimulated vesicular exocytosis that persisted many minutes after the exposure. The kinetics of NPPB-evoked exocytosis and ATP release were similar. Furthermore, the magnitudes of NPPB-evoked exocytosis and ATP release were correlated (correlation coefficient 0.77), indicating that NPPB may stimulate exocytosis of a pool of ATP-enriched vesicles. These findings provide further support for the concept that vesicular exocytosis plays an important role in cellular ATP release and suggest that NPPB can be used as a biochemical tool to specifically stimulate ATP release through exocytic mechanisms.

There is a rise in the number of people who have vision loss due to retinal diseases, and conventional therapies for treating retinal degeneration fail to repair and regenerate the damaged retina. Several studies in animal models and human trials have explored the use of stem cells to repair the retinal tissue to improve visual acuity. In addition to the treatment of age-related macular degeneration (AMD) and diabetic retinopathy (DR), stem cell therapies were used to treat genetic diseases such as retinitis pigmentosa (RP) and Stargardt’s disease, characterized by gradual loss of photoreceptor cells in the retina. Transplantation of retinal pigment epithelial (RPE) cells derived from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have shown promising results in improving retinal function in various preclinical models of retinal degeneration and clinical studies without any severe side effects. Mesenchymal stem cells (MSCs) were utilized to treat optic neuropathy, RP, DR, and glaucoma with positive clinical outcomes. This review summarizes the preclinical and clinical evidence of stem cell therapy and current limitations in utilizing stem cells for retinal degeneration.

Relationship between macular and retinal diseases with prevalent atrial fibrillation — An analysis of the Australian Heart Eye Study

Editor, Recent population-based studies on Caucasians have shown that smokers have an increased risk for age-related macular degeneration (Thornton et al. 2005; de Jong 2006). Because the smoking habits vary between different cultures and because there have been no population-based data on the associations between smoking and ocular normative parameters and ophthalmic diseases for the Chinese population of mainland China, we conducted the present study to assess the associations between smoking and ophthalmic parameters and selected systemic parameters in China. The Beijing Eye Study is a population-based cross-sectional study in Northern China. It has been described in detail recently (Jonas et al. 2009). First performed in the year 2001, the study was repeated in 2006, with 3251 subjects participating. The study participants underwent a detailed ophthalmic examination and answered a questionnaire including questions on current and former smoking and the mean number of packages smoked per day. Information on smoking was obtained from 3214 (98.9%) subjects. There were 725 (22.6%) current smokers, 1042 (32.4%) current or former smokers and 2172 (67.6%) never smokers. In univariate analysis, the prevalence of current smoking/former smoking was significantly (p < 0.01) associated with male gender, rural region, hyperopic refractive error, lower serum levels of high-density lipoproteins and low-density lipoproteins, a lower level of education and income, higher diastolic and systolic blood pressure, a higher mortality, a more shallow anterior chamber, a lower prevalence of dry eye symptoms, a higher prevalence of pterygium, a higher prevalence of trachoma, and thinner retinal arteries and veins. Smokers and nonsmokers did not vary significantly in age, the prevalences of open-angle glaucoma, angle-closure glaucoma, nonglaucomatous optic nerve atrophy, age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, myelinated retinal nerve fibers, alpha zone and beta zone of parapapillary atrophy and retinal vein occlusions. In binary logistic regression analysis, current/former smoking versus never smoking was significantly associated with male gender, hyperopic refractive error, rural region, lower level of education and higher intraocular pressure (Table 1). It was marginally significant with mean blood pressure. If the analysis additionally included the serum levels of cholesterol, high-density lipoproteins and low-density lipoproteins, only an elevated serum concentration of cholesterol was additionally associated with smoking (p = 0.05). Interestingly, the multivariate analysis showed that smokers were significantly more hyperopic than the never smokers. This may have clinical importance for ophthalmic disorders, because some ocular diseases are associated with the refractive error. To cite examples, previous studies such as the Rotterdam Study and the Beijing Eye Study have revealed that hyperopia is associated with an increased prevalence of age-related macular degeneration, diabetic retinopathy and angle-closure glaucoma (Ikram et al. 2003; Xu et al. 2006). If in the assessment of the relationships between smoking and these ocular diseases the refractive error as a potentially confounding factor was not taken into account, the correlation between smoking and these diseases may become artificially statistically significant. Smoking was associated with a lower socioeconomic background. Because the socioeconomic background plays a role in the development and progression of diseases, the association between smoking and a low socioeconomic background may have to be taken into account if the role of smoking for the development of progression of ocular diseases is examined. In the multivariate analysis, smoking was not significantly associated with alpha zone and beta zone of parapapillary atrophy. It agrees with previous studies in which parapapillary atrophy was not related to other vascular parameters such as arterial hypertension (Jonas & Gründler 1996). The prevalence of early age-related macular degeneration was not markedly associated with smoking. It agrees with the Copenhagen City Eye Study (Buch et al. 2005), and it contradicts previous population-based studies examining other ethnic groups (Thornton et al. 2005; de Jong 2006). Reason for the discrepancies between these studies may potentially be differences in the statistical analysis, if the potentially confounding associations between smoking, hyperopia and age-related macular degeneration were not sufficiently taken into account. In the present investigation, smoking was not associated with the prevalence of glaucoma. It is in agreement with the recent Los Angeles Latino Eye Study (Doshi et al. 2008). In conclusion, smoking was significantly associated with male gender, rural region, lower level of education, elevated serum concentration of cholesterol, hyperopia and higher intraocular pressure in the adult population of mainland China. In contrast to studies on Western ethnic groups, smoking was not markedly associated with the prevalence of age-related macular degeneration, nor of glaucoma or retinal vein occlusions. The association between smoking as dependent parameter and hyperopia and lower level of education as independent factors may have to be considered when the role of smoking for ocular diseases, particularly for age-related macular degeneration, is examined. Supported by the Beijing Natural Science Foundation.

Gene therapy to treat inherited and complex retinal degenerative diseases

An Adenosine Analogue Inhibits NMDA Receptor-Mediated Responses in Bipolar Cells of the Rat Retina