Steroid-Induced Ocular Hypertension in Mice Is Differentially Reduced by Selective EP2, EP3, EP4, and IP Prostanoid Receptor Agonists.

We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 µg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.

Human experience and efficacy of omidenepag isopropyl (Eybelis®; Omlonti®): Discovery to approval of the novel non-prostaglandin EP2-receptor-selective agonist ocular hypotensive drug.

More than 75 million people worldwide suffer from ocular hypertension (OHT)-associated retinal and optic nerve degenerative diseases that cause visual impairment and can lead to blindness. In an effort to find novel pharmaceutical therapeutics to combat OHT with reduced side-effect potential, several emerging drug candidates have advanced to human proof-of-concept in recent years. One such compound is a nonprostaglandin (non-PG) EP2-receptor-selective agonist (omidenepag isopropyl ester). Omidenepag (OMD; free acid form) is a novel non-PG that selectively binds to and activates the human EP2-prostglandin receptor (EP2R) with a high affinity (Ki = 3.6 nM) and which potently generates intracellular cAMP in living cells (EC50 = 3.9-8.3 nM). OMD significantly downregulated COL12A1 and COL13A1 mRNAs in human trabecular meshwork (TM) cells, a tissue involved in the pathogenesis of OHT. Omidenepag isopropyl (OMDI) potently and efficaciously lowered intraocular pressure (IOP) in ocular normotensive rabbits, dogs, and monkeys, and also in ocular hypertension (OHT) Cynomolgus monkeys, after a single topical ocular (t.o.) instillation at doses of 0.0001-0.01%. No reduction in IOP-lowering response to OMDI was observed after repeated t.o. dosing with OMDI in dogs and monkeys. Additive IOP reduction to OMDI was noted with brinzolamide, timolol, and brimonidine in rabbits and monkeys. OMDI 0.002% t.o. decreased IOP by stimulating the conventional (TM) and uveoscleral (UVSC) outflow of aqueous humor (AQH) in OHT monkeys. In a Phase-III clinical investigation, 0.002% OMDI (once daily t.o.) reduced IOP by 5-6 mmHg in OHT/primary open-angle glaucoma (POAG) patients (22-34 mmHg baseline IOPs) that was maintained over 12-months. In an additional month-long clinical study, 0.002% OMDI induced IOP-lowering equivalent to that of latanoprost (0.005%), a prostanoid FP-receptor agonist, thus OMDI was noninferior to latanoprost. Additive IOPreduction was also noted in OHT/OAG patients when OMDI (0.002%, once daily t.o.) and timolol (0.05%, twice daily t.o.) were administered. Patients with OHT/POAG who were low responders or nonresponders to latanoprost (0.005%, q.d.; t.o.) experienced significant IOP-lowering (additional approximately 3 mmHg) when they were switched over to OMDI 0.002% (q.d.; t.o.). No systemic or ocular adverse reactions (e.g. iris color changes/deepening of the upper eyelid sulcus/abnormal eyelash growth) were noted after a year-long, once-daily t.o. dosing with 0.002 % OMDI in OHT/POAG patients. However, OMDI caused transient conjunctival hyperemia. These characteristics of OMDI render it a suitable new medication for treating OHT and various types of glaucoma, especially where elevated IOP is implicated.

Gene therapies and gene product-based drug candidates for normalizing and preserving tissue functions in animal models of ocular hypertension and glaucoma.

More than 76 million people worldwide are afflicted with the neurodegenerative eye diseases described and grouped together as glaucoma. A common feature amongst the many forms of glaucoma is chronically elevated intraocular pressure (IOP) within the anterior chamber of the eye that physically damages the retina, optic nerve and parts of the brain connected with visual perception. The mediators of the contusing raised IOP responsible for such damage and loss of vision include locally released inflammatory agents, tissue remodeling enzymes and infiltrating immune cells which damage the retinal ganglion cell (RGC) axons and eventually kill a significant number of the RGCs. Additional culprits include genetic defects of the patient that involve aberrations in receptors, enzymes and/or endogenous ligands and possible over- or under-production of the latter. Other genetic abnormalities may include issues with signal transduction machinery within key cells of critical tissues in the front (e.g. trabecular meshwork [TM] and Schlemm's canal [SC]) and back of the eye (e.g. retinal ganglion cells and their axons). Genome-wide associated studies (GWAS) coupled with next generation sequencing have provided powerful linkage of certain gene defects and polymorphic variants to the onset and progression of diseases of the tissues involved in fluid dynamics in the TM and SC, and many retinal elements (lamina cribosa, optic nerve head) at the back of the eye which cause ocular hypertension (OHT) and glaucomatous optic neuropathy (GON), respectively. Despite the availability of some drugs, fluid drainage microshunts and full surgical techniques to lower and control intraocular pressure, the major modifiable biomarker of open-angle and other forms of glaucoma, their side-effect profiles, less than optimum effectiveness and short duration of action present opportunities to clinically manage the glaucomas with next generation of treatments with high therapeutic indices, including gene therapies. Thus, identification, characterization and deployment of genetic data coupled with traditional drug discovery and novel gene replacement, gene editing and genetic engineering technologies may provide some solutions to the aforementioned problems. These aspects will be discussed in this article.

Ocular Treatments Targeting Separate Prostaglandin Receptors in Mice Exhibit Alterations in Intraocular Pressure and Optic Nerve Lipidome.

Background: Prostaglandin (PG) receptor agonists are the first-line eyedrop medication treatment for glaucoma. The pathophysiology of this disease is not completely known, and elevated intraocular pressure (IOP) is the key risk factor. The membranes of the axons (of the retinal ganglion cells) passing through the optic nerve (ON) head experience significant damage. Lipids are an essential component of the cell's membranes, and their profile changes owing to neurodegeneration. In this investigation, three agonists for distinct PG receptors were used to lower IOP and to determine their effect on the ON lipids. We utilized DBA/2J mice as a model of progressive IOP increase and C57BL/6J mice as a model of ON crush. Methods: DBA/2J and C57BL/6J mice were treated daily for 2 weeks with Latanoprost, PF-04217329, or Rivenprost. The IOP was measured every 2 days and pattern electroretinogram was conducted for DBA/2J throughout the study. Lipidomics of ONs were performed for each model and treatment group. Results: Of the tested compounds, Latanoprost and Rivenprost were the most effective agents decreasing IOP in DBA/2J mice. Triglyceride levels increased in the ONs of DBA/2J mouse model, but phosphatidylethanolamine levels underwent highest level changes in the C57BL/6J mouse model when treated with Latanoprost. Conclusions: Topical ocular FP- and EP4-receptor agonists appreciably lowered IOP in the DBA/2J mice representing pigmentary glaucoma. The observed changes in ON lipidomics in the different models of neurodegeneration suggest possible use of such measures in the development of more effective medicines for both IOP reduction and ON protection.

Recently Approved Drugs for Lowering and Controlling Intraocular Pressure to Reduce Vision Loss in Ocular Hypertensive and Glaucoma Patients.

Serious vision loss occurs in patients affected by chronically raised intraocular pressure (IOP), a characteristic of many forms of glaucoma where damage to the optic nerve components causes progressive degeneration of retinal and brain neurons involved in visual perception. While many risk factors abound and have been validated for this glaucomatous optic neuropathy (GON), the major one is ocular hypertension (OHT), which results from the accumulation of excess aqueous humor (AQH) fluid in the anterior chamber of the eye. Millions around the world suffer from this asymptomatic and progressive degenerative eye disease. Since clinical evidence has revealed a strong correlation between the reduction in elevated IOP/OHT and GON progression, many drugs, devices, and surgical techniques have been developed to lower and control IOP. The constant quest for new pharmaceuticals and other modalities with superior therapeutic indices has recently yielded health authority-approved novel drugs with unique pharmacological signatures and mechanism(s) of action and AQH drainage microdevices for effectively and durably treating OHT. A unique nitric oxide-donating conjugate of latanoprost, an FP-receptor prostaglandin (PG; latanoprostene bunod), new rho kinase inhibitors (ripasudil; netarsudil), a novel non-PG EP2-receptor-selective agonist (omidenepag isopropyl), and a form of FP-receptor PG in a slow-release intracameral implant (Durysta) represent the additions to the pharmaceutical toolchest to mitigate the ravages of OHT. Despite these advances, early diagnosis of OHT and glaucoma still lags behind and would benefit from further concerted effort and attention.

Elevated Intraocular Pressure and Glaucomatous Optic Neuropathy: Genes to Disease Mechanisms, Therapeutic Drugs, and Gene Therapies.

This review article focuses on the pathogenesis of and genetic defects linked with chronic ocular hypertension (cOHT) and glaucoma. The latter ocular disease constitutes a group of ocular degenerative diseases whose hallmark features are damage to the optic nerve, apoptotic demise of retinal ganglion cells, disturbances within the brain regions involved in visual perception and considerable visual impairment that can lead to blindness. Even though a number of pharmaceuticals, surgical and device-based treatments already exist addressing cOHT associated with the most prevalent of the glaucoma types, primary open-angle glaucoma (POAG), they can be improved upon in terms of superior efficacy with reduced side-effects and with longer duration of activity. The linkage of disease pathology to certain genes via genome-wide associated studies are illuminating new approaches to finding novel treatment options for the aforementioned ocular disorders. Gene replacement, gene editing via CRISPR-Cas9, and the use of optogenetic technologies may replace traditional drug-based therapies and/or they may augment existing therapeutics for the treatment of cOHT and POAG in the future.

Identifying new drugs and targets to treat rapidly elevated intraocular pressure for angle closure and secondary glaucomas to curb visual impairment and prevent blindness.

A multitude of pharmacological compounds have been shown to lower and control intraocular pressure (IOP) in numerous species of animals and human subjects after topical ocular dosing or via other routes of administration. Most researchers have been interested in finding drug candidates that exhibit a relatively long duration of action from a chronic therapeutic use perspective, for example to treat ocular hypertension (OHT), primary open-angle glaucoma and even normotensive glaucoma. However, it is equally important to seek and characterize treatment modalities which offer a rapid onset of action to help provide fast relief from quickly rising IOP that occurs in certain eye diseases. These include acute angle-closure glaucoma, primary angle-closure glaucoma, uveitic and inflammatory glaucoma, medication-induced OHT, and other secondary glaucomas induced by eye injury or infection which can cause partial or complete loss of eyesight. Such fast-acting agents can delay or prevent the need for ocular surgery which is often used to lower the dangerously raised IOP. This research survey was therefore directed at identifying agents from the literature that demonstrated ocular hypotensive activity, normalizing and unifying the data, determining their onset of action and rank ordering them on the basis of rapidity of action starting within 30-60 min and lasting up to at least 3-4 h post topical ocular dosing in different animal species. This research revealed a few health authority-approved drugs and some investigational compounds that appear to meet the necessary criteria of fast onset of action coupled with significant efficacy to reduce elevated IOP (by ≥ 20%, preferably by >30%). However, translation of the novel animal-based findings to the human conditions remains to be demonstrated but represent viable targets, especially EP2-receptor agonists (e.g. omidenepag isopropyl; AL-6598; butaprost), mixed activity serotonin/dopamine receptor agonists (e.g. cabergoline), rho kinase inhibitors (e.g. AMA0076, Y39983), CACNA2D1-gene product inhibitors (e.g. pregabalin), melatonin receptor agonists, and certain K+-channel openers (e.g. nicorandil, pinacidil). Other drug candidates and targets were also identified and will be discussed.

FP and EP2 prostanoid receptor agonist drugs and aqueous humor outflow devices for treating ocular hypertension and glaucoma.

Prostaglandin (PG) receptors represent important druggable targets due to the many diverse actions of PGs in the body. From an ocular perspective, the discovery, development, and health agency approvals of prostaglandin F (FP) receptor agonists (FPAs) have revolutionized the medical treatment of ocular hypertension (OHT) and glaucoma. FPAs, such as latanoprost, travoprost, bimatoprost, and tafluprost, powerfully lower and control intraocular pressure (IOP), and became first-line therapeutics to treat this leading cause of blindness in the late 1990s to early 2000s. More recently, a latanoprost-nitric oxide (NO) donor conjugate, latanoprostene bunod, and a novel FP/EP3 receptor dual agonist, sepetaprost (ONO-9054 or DE-126), have also demonstrated robust IOP-reducing activity. Moreover, a selective non-PG prostanoid EP2 receptor agonist, omidenepag isopropyl (OMDI), was discovered, characterized, and has been approved in the United States, Japan and several other Asian countries for treating OHT/glaucoma. FPAs primarily enhance uveoscleral (UVSC) outflow of aqueous humor (AQH) to reduce IOP, but cause darkening of the iris and periorbital skin, uneven thickening and elongation of eyelashes, and deepening of the upper eyelid sulcus during chronic treatment. In contrast, OMDI lowers and controls IOP by activation of both the UVSC and trabecular meshwork outflow pathways, and it has a lower propensity to induce the aforementioned FPA-induced ocular side effects. Another means to address OHT is to physically promote the drainage of the AQH from the anterior chamber of the eye of patients with OHT/glaucoma. This has successfully been achieved by the recent approval and introduction of miniature devices into the anterior chamber by minimally invasive glaucoma surgeries. This review covers the three major aspects mentioned above to highlight the etiology of OHT/glaucoma, and the pharmacotherapeutics and devices that can be used to combat this blinding ocular disease.

Neuroaxonal and cellular damage/protection by prostanoid receptor ligands, fatty acid derivatives and associated enzyme inhibitors.

Cellular and mitochondrial membrane phospholipids provide the substrate for synthesis and release of prostaglandins in response to certain chemical, mechanical, noxious and other stimuli. Prostaglandin D2, prostaglandin E2, prostaglandin F2α, prostaglandin I2 and thromboxane-A2 interact with five major receptors (and their sub-types) to elicit specific downstream cellular and tissue actions. In general, prostaglandins have been associated with pain, inflammation, and edema when they are present at high local concentrations and involved on a chronic basis. However, in acute settings, certain endogenous and exogenous prostaglandins have beneficial effects ranging from mediating muscle contraction/relaxation, providing cellular protection, regulating sleep, and enhancing blood flow, to lowering intraocular pressure to prevent the development of glaucoma, a blinding disease. Several classes of prostaglandins are implicated (or are considered beneficial) in certain central nervous system dysfunctions (e.g., Alzheimer's, Parkinson's, and Huntington's diseases; amyotrophic lateral sclerosis and multiple sclerosis; stroke, traumatic brain injuries and pain) and in ocular disorders (e.g., ocular hypertension and glaucoma; allergy and inflammation; edematous retinal disorders). This review endeavors to address the physiological/pathological roles of prostaglandins in the central nervous system and ocular function in health and disease, and provides insights towards the therapeutic utility of some prostaglandin agonists and antagonists, polyunsaturated fatty acids, and cyclooxygenase inhibitors.

Electrical, Electromagnetic, Ultrasound Wave Therapies, and Electronic Implants for Neuronal Rejuvenation, Neuroprotection, Axonal Regeneration, and IOP Reduction.

The peripheral nervous system (PNS) of mammals and nervous systems of lower organisms possess significant regenerative potential. In contrast, although neural plasticity can provide some compensation, the central nervous system (CNS) neurons and nerves of adult mammals generally fail to regenerate after an injury or damage. However, use of diverse electrical, electromagnetic and sonographic energy waves are illuminating novel ways to stimulate neuronal differentiation, proliferation, neurite growth, and axonal elongation/regeneration leading to various levels of functional recovery in animals and humans afflicted with disorders of the CNS, PNS, retina, and optic nerve. Tools such as acupuncture, electroacupuncture, electroshock therapy, electrical stimulation, transcranial magnetic stimulation, red light therapy, and low-intensity pulsed ultrasound therapy are demonstrating efficacy in treating many different maladies. These include wound healing, partial recovery from motor dysfunctions, recovery from ischemic/reperfusion insults and CNS and ocular remyelination, retinal ganglion cell (RGC) rejuvenation, and RGC axonal regeneration. Neural rejuvenation and axonal growth/regeneration processes involve activation or intensifying of the intrinsic bioelectric waves (action potentials) that exist in every neuronal circuit of the body. In addition, reparative factors released at the nerve terminals and via neuronal dendrites (transmitter substances), extracellular vesicles containing microRNAs and neurotrophins, and intercellular communication occurring via nanotubes aid in reestablishing lost or damaged connections between the traumatized tissues and the PNS and CNS. Many other beneficial effects of the aforementioned treatment paradigms are mediated via gene expression alterations such as downregulation of inflammatory and death-signal genes and upregulation of neuroprotective and cytoprotective genes. These varied techniques and technologies will be described and discussed covering cell-based and animal model-based studies. Data from clinical applications and linkage to human ocular diseases will also be discussed where relevant translational research has been reported.

MicroRNA profile of extracellular vesicles released by Müller glial cells.

Introduction: As with any other radial glia in the central nervous system, Müller glia derive from the same neuroepithelial precursors, perform similar functions, and exhibit neurogenic properties as radial glia in the brain. Müller glial cells retain progenitor-like characteristics in the adult human eye and can partially restore visual function upon intravitreal transplantation into animal models of glaucoma. Recently, it has been demonstrated that intracellular communication is possible via the secretion of nano-sized membrane-bound extracellular vesicles (EV), which contain bioactive molecules like microRNA (miRNA) and proteins that induce phenotypic changes when internalised by recipient cells. Methods: We conducted high-throughput sequencing to profile the microRNA signature of EV populations secreted by Müller glia in culture and used bioinformatics tools to evaluate their potential role in the neuroprotective signalling attributed to these cells. Results: Sequencing of miRNA within Müller EV suggested enrichment with species associated with stem cells such as miR-21 and miR-16, as well as with miRNA previously found to play a role in diverse Müller cell functions in the retina: miR-9, miR-125b, and the let-7 family. A total of 51 miRNAs were found to be differentially enriched in EV compared to the whole cells from which EV originated. Bioinformatics analyses also indicated that preferential enrichment of species was demonstrated to regulate genes involved in cell proliferation and survival, including PTEN, the master inhibitor of the PI3K/AKT pathway. Discussion: The results suggest that the release by Müller cells of miRNA-enriched EV abundant in species that regulate anti-apoptotic signalling networks is likely to represent a significant proportion of the neuroprotective effect observed after the transplantation of these cells into animal models of retinal ganglion cell (RGC) depletion. Future studies will seek to evaluate the modulation of putative genes as well as the activation of these pathways in in vitro and in vivo models following the internalisation of Müller-EV by target retinal neurons.

Neuroprotection in neurodegenerations of the brain and eye: Lessons from the past and directions for the future.

Background: Neurological and ophthalmological neurodegenerative diseases in large part share underlying biology and pathophysiology. Despite extensive preclinical research on neuroprotection that in many cases bridges and unifies both fields, only a handful of neuroprotective therapies have succeeded clinically in either. Main body: Understanding the commonalities among brain and neuroretinal neurodegenerations can help develop innovative ways to improve translational success in neuroprotection research and emerging therapies. To do this, analysis of why translational research in neuroprotection fails necessitates addressing roadblocks at basic research and clinical trial levels. These include optimizing translational approaches with respect to biomarkers, therapeutic targets, treatments, animal models, and regulatory pathways. Conclusion: The common features of neurological and ophthalmological neurodegenerations are useful for outlining a path forward that should increase the likelihood of translational success in neuroprotective therapies.

PAF-induced inflammatory and immuno-allergic ophthalmic diseases and their mitigation with PAF receptor antagonists: Cell and nuclear effects.

Ocular allergies are becoming more prevalent as more airborne pollutants, irritants and microbes pervade our environment. Inflammatory and allergic mediators released by dendritic and mast cells within the conjunctiva cause allergic conjunctivitis (AC), a prevalent ocular surface disorder that affects >40% of the world's human population on a seasonal or perennial basis. Even though histamine is a major culprit, platelet-activating factor (PAF) also contributes to AC, acting either directly or synergistically with histamine and other mediators. PAF receptor-meditated inflammatory reactions, via cell-membrane-bound and nuclear-membrane-bound and nuclear PAF receptors, are also implicated in the etiology of other eye diseases such as uveitis, diabetic retinopathy, corneal and choroidal neovascularization, and age-related macular degeneration which cause serious visual impairment and can lead to blindness. This review highlights the various deleterious elements implicated in the pathological aspects of ocular allergic reactions and inflammation and provides concepts and treatment options to mitigate these eye disorders with a special focus on PAF and PAF receptor antagonists.

Degeneration of retina-brain components and connections in glaucoma: Disease causation and treatment options for eyesight preservation.

Eyesight is the most important of our sensory systems for optimal daily activities and overall survival. Patients who experience visual impairment due to elevated intraocular pressure (IOP) are often those afflicted with primary open-angle glaucoma (POAG) which slowly robs them of their vision unless treatment is administered soon after diagnosis. The hallmark features of POAG and other forms of glaucoma are damaged optic nerve, retinal ganglion cell (RGC) loss and atrophied RGC axons connecting to various brain regions associated with receipt of visual input from the eyes and eventual decoding and perception of images in the visual cortex. Even though increased IOP is the major risk factor for POAG, the disease is caused by many injurious chemicals and events that progress slowly within all components of the eye-brain visual axis. Lowering of IOP mitigates the damage to some extent with existing drugs, surgical and device implantation therapeutic interventions. However, since multifactorial degenerative processes occur during aging and with glaucomatous optic neuropathy, different forms of neuroprotective, nutraceutical and electroceutical regenerative and revitalizing agents and processes are being considered to combat these eye-brain disorders. These aspects form the basis of this short review article.

Therapeutic Drugs and Devices for Tackling Ocular Hypertension and Glaucoma, and Need for Neuroprotection and Cytoprotective Therapies.

Damage to the optic nerve and the death of associated retinal ganglion cells (RGCs) by elevated intraocular pressure (IOP), also known as glaucoma, is responsible for visual impairment and blindness in millions of people worldwide. The ocular hypertension (OHT) and the deleterious mechanical forces it exerts at the back of the eye, at the level of the optic nerve head/optic disc and lamina cribosa, is the only modifiable risk factor associated with glaucoma that can be treated. The elevated IOP occurs due to the inability of accumulated aqueous humor (AQH) to egress from the anterior chamber of the eye due to occlusion of the major outflow pathway, the trabecular meshwork (TM) and Schlemm's canal (SC). Several different classes of pharmaceutical agents, surgical techniques and implantable devices have been developed to lower and control IOP. First-line drugs to promote AQH outflow via the uveoscleral outflow pathway include FP-receptor prostaglandin (PG) agonists (e.g., latanoprost, travoprost and tafluprost) and a novel non-PG EP2-receptor agonist (omidenepag isopropyl, Eybelis®). TM/SC outflow enhancing drugs are also effective ocular hypotensive agents (e.g., rho kinase inhibitors like ripasudil and netarsudil; and latanoprostene bunod, a conjugate of a nitric oxide donor and latanoprost). One of the most effective anterior chamber AQH microshunt devices is the Preserflo® microshunt which can lower IOP down to 10-13 mmHg. Other IOP-lowering drugs and devices on the horizon will be also discussed. Additionally, since elevated IOP is only one of many risk factors for development of glaucomatous optic neuropathy, a treatise of the role of inflammatory neurodegeneration of the optic nerve and retinal ganglion cells and appropriate neuroprotective strategies to mitigate this disease will also be reviewed and discussed.

The Role of Autophagy in Chemical Proteasome Inhibition Model of Retinal Degeneration.

We recently demonstrated that chemical proteasome inhibition induced inner retinal degeneration, supporting the pivotal roles of the ubiquitin-proteasome system in retinal structural integrity maintenance. In this study, using beclin1-heterozygous (Becn1-Het) mice with autophagic dysfunction, we tested our hypothesis that autophagy could be a compensatory retinal protective mechanism for proteasomal impairment. Despite the reduced number of autophagosome, the ocular tissue morphology and intraocular pressure were normal. Surprisingly, Becn1-Het mice experienced the same extent of retinal degeneration as was observed in wild-type mice, following an intravitreal injection of a chemical proteasome inhibitor. Similarly, these mice equally responded to other chemical insults, including endoplasmic reticulum stress inducer, N-methyl-D-aspartate, and lipopolysaccharide. Interestingly, in cultured neuroblastoma cells, we found that the mammalian target of rapamycin-independent autophagy activators, lithium chloride and rilmenidine, rescued these cells against proteasome inhibition-induced death. These results suggest that Becn1-mediated autophagy is not an effective intrinsic protective mechanism for retinal damage induced by insults, including impaired proteasomal activity; furthermore, autophagic activation beyond normal levels is required to alleviate the cytotoxic effect of proteasomal inhibition. Further studies are underway to delineate the precise roles of different forms of autophagy, and investigate the effects of their activation in rescuing retinal neurons under various pathological conditions.

Discovery to Launch of Anti-allergy (Emadine; Patanol/Pataday/Pazeo) and Anti-glaucoma (Travatan; Simbrinza) Ocular Drugs, and Generation of Novel Pharmacological Tools Such as AL-8810.

The eye and eyesight are exquistly designed and are precious, and yet we often take them for granted. Good vision is critical for our long-term survival and for humanity's enduring progress. Unfortunately, since ocular diseases do not culminate in life-and-death scenarios, awareness of the plight of millions of people suffering from such eye ailments is not publicized as other diseases. However, losing eyesight or falling victim to visual impairment is a frightening outlook for most people. Glaucoma, a collection of chronic optic neuropathies, of which the most prevalent form, primary open-angle glaucoma (POAG), is the second leading cause of irreversible blindness. POAG currently afflicts >70 million people worldwide and is an insidious, progressive, silent thief of sight that is asymptomatic. On the other hand, allergic conjunctivitis (AC), and the associated rhinitis ("hay-fever"), frequently victimizes a huge number of people worldwide, especially during seasonal changes. While not life-threatening, sufferers of AC soon learn the value of drugs to treat their signs and symptoms of AC as they desire rapid relief to overcome the ocular itching/pain, redness, and tearing AC causes. Herein, I will describe the collective efforts of many researchers whose industrious, diligent, and dedicated team work resulted in the discovery, biochemical/pharmacological characterization, development and eventual launch of drugs to treat AC (e.g., olopatadine [Patanol/Pataday/Pazeo] and emedastine [Emedine]), and for treating ocular hypertension and POAG (e.g., travoprost [Travatan ] and Simbrinza). This represents a personal perspective.

Prostaglandin FP receptor antagonists: discovery, pharmacological characterization and therapeutic utility.

In contrast to the availability of potent and selective antagonists of several prostaglandin receptor types (including DP1 , DP2 , EP and TP receptors), there has been a paucity of well-characterized, selective FP receptor antagonists. The earliest ones included dimethyl amide and dimethyl amine derivatives of PGF2α , but these have failed to gain prominence. The fluorinated PGF2α analogues, AL-8810 and AL-3138, were subsequently discovered as competitive and non-competitive FP receptor antagonists respectively. Non-prostanoid structures, such as the thiazolidinone AS604872, the D-amino acid-based oligopeptide PDC31 and its peptidomimic analogue PDC113.824 came next, but the latter two are allosteric inhibitors of FP receptor signalling. AL-8810 has a sub-micromolar in vitro potency and ≥2 log unit selectivity against most other PG receptors when tested in several cell- and tissue-based functional assays. Additionally, AL-8810 has demonstrated therapeutic efficacy as an FP receptor antagonist in animal models of stroke, traumatic brain injury, multiple sclerosis, allodynia and endometriosis. Consequently, it appears that AL-8810 has become the FP receptor antagonist of choice. LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.

Discovery, characterization and clinical utility of prostaglandin agonists for the treatment of glaucoma.

Topical ophthalmic formulations of analogues of the endogenous arachidonic acid cyclooxygenase metabolite, PGF2α , are the standard of care treatment for the blinding disease glaucoma. These are the most potent and efficacious medical therapies for lowering intraocular pressure (IOP), the most important risk factor identified for disease progression. They have few side effects and offer the convenience of once-a-day dosing. It was initially believed that endogenous PGs raised IOP and caused substantial ocular surface adverse effects. However, carefully designed experiments demonstrated that esterification of the carboxylic acid afforded potent and efficacious topical ocular hypotensive activity. The final hurdle to be overcome was improvement of the side effect profile. A hypothesis was advanced that the IOP-lowering effect of PGF2α isopropyl ester was due to activation of its cognate PG-FP receptor, while side effects were largely due to promiscuous interaction with other PG receptors. This hypothesis was validated by modification of the ω chain (carbons 13-20) to a phenyl group. This provided the first marketed FP-class PG agonist analogue (FP-PGA) ocular hypotensive agent, latanoprost. Since the introduction of latanoprost into clinical medicine to lower and control IOP, a number of additional FP-PGAs have been discovered, characterized and marketed, including travoprost, tafluprost, unoprostone isopropyl ester and bimatoprost (an amide). LINKED ARTICLES: This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.

Glaucomatous optic neuropathy treatment options: the promise of novel therapeutics, techniques and tools to help preserve vision.

Peripheral vision loss followed by "tunnel vision" and eventual irreversible blindness is the fate of patients afflicted by various forms of glaucoma including primary open-angle glaucoma (POAG) and normotensive glaucoma (NTG). These complex and heterogeneous diseases are characterized by extensive death of retinal ganglion cells (RGCs) accompanied by retraction and severance of their axonal connections to the brain and thus damage to and thinning of the optic nerve. Since patients suffering from this glaucomatous optic neuropathy (GON) first notice visual impairment when they have lost > 40% of their RGCs, early diagnosis is the key to retard the progression of glaucoma. Elevated intraocular pressure (IOP), low cerebrospinal and/or low intracranial fluid pressure, advancing age, and ethnicity are major risk factors associated with POAG. However, retinal vascular abnormalities and a high sensitivity of RGCs and optic nerve head components to neurotoxic, inflammatory, oxidative and mechanical insults also contribute to vision loss in POAG/GON. Current treatment modalities for POAG and NTG involve lowering IOP using topical ocular drugs, combination drug products, and surgical interventions. Two recently approved multi-pharmacophoric drugs (e.g., rho kinase inhibitor, Netarsudil; a drug conjugate, Latanoprostene Bunod) and novel aqueous humor drainage devices (iStent and CyPass) are also gaining acceptance for treating POAG/ NTG. Neuroprotective and regenerative agents, coupled with electroceutical, mechanical support systems, stem cell transplantation and gene therapy are emerging therapeutics on the horizon to help combat GON. The latter techniques and approaches hope to rejuvenate RGCs and repair the optic nerve structures, thereby providing a gain of function of the visual system for the glaucoma patients.