Abstract
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Although current and recent drugs introduced into clinical practice for glaucoma/OHT treatment primarily reduce AQH production (eg, timolol and brimonidine) or enhance uveoscleral outflow [f-prostaglandin-receptor agonist prostaglandins (PGs) such as latanoprost and travoprost], there has been a paucity of drugs addressing conventional trabecular meshwork (TM) outflow. Now, one of the articles in this Volume 1 (Lin et al.) presents a new drug that targets the TM, the diseased pathway that leads to the elevation of IOP in the first place. This agent (netarsudil) inhibits Rho-associated kinase and relaxes cells of the TM and Schlemm's canal, decreases expression of extracellular matrix proteins, and reduces the stiffness of TM and Schlemm's canal cells, leading to enhancement of TM outflow facility and thus reduction in IOP.
There is also an article demonstrating the ocular hypotensive efficacy of combining a PG analog with a nitric oxide (NO) donor in one molecule (Cavet and DeCory). This interesting conjugate drug (latanoprostene bunod) ultimately releases the PG to enhance uveoscleral outflow and an NO donor that enhances outflow through the conventional TM pathway. Another article shows that hydrogen sulfide donor compounds can also lower IOP in rabbits (Ohia et al.), thus extending the utility of gaseous molecules in promoting AQH outflow to decrease IOP. It is well known now that serotonin receptor-2A (5-HT2A) agonists lower IOP in ocular hypertensive monkeys. However, in Volume 1, two articles (Ohia et al., and Njie-Mbye et al.) provide pharmacological evidence, using receptor-selective agonists and antagonists, that bovine ciliary muscle and posterior ciliary artery contraction are predominantly mediated by 5-HT2B/2C receptors. These data suggest potential species differences in the 5-HT receptors involved in modulation of IOP and of ocular blood flow, and these aspects need to be considered in future drug discovery and development of such class of drugs.
Even though vision loss in OHT/Primary Open-Angle Glaucoma (POAG) patients is slowed down by IOP reduction, patients who are ocular normotensive continue to lose peripheral vision. Consequently, means to directly protect RGCs and their axons are urgently needed. A number of reviews in Volume 1 address such neuroprotective strategies. The potential etiologies, targets, and sites of intervention within the visual axis for treating GON, coupled with characterization of neuroprotective agents, are described in reviews by He et al., Sharif, and by De Groef and Cordeiro. Combined IOP regulation and RGC protection by delta opioid agonists represents a new area of ocular study (reviewed by Husain), as is curtailing retinal toxicity by preventing excess release of excitatory amino acids (reviewed by Opere et al.). Thus, even though several retinoprotective agents have been discovered from cell-based studies and from animal models of GON, there has yet to be an approved drug for glaucoma that has as its primary action through neuroprotection.
Part of the problem is that POAG is a slow developing disease, and by the time it is identified, as many as 40% of RGCs have already been lost. Identifying the disease early in development may depend on applying precise early biomarkers that can predict development of glaucoma so that intervention can proceed before significant loss of RGCs occurs. Such a diagnostic/prognostic agent to help monitor RGC loss or preservation appears to be fluorescently labeled annexin-5 that detects apoptosing retinal cells (DARC; pioneered by Cordiero's group). Drawing upon similarities between the neurodegenerative diseases of the central nervous system and GON, the utility of DARC in animal studies and in recent human clinical trials to map retinal cell loss seems exciting and important (De Groef and Cordeiro).
POAG and GON are obviously a set of complex intertwined neurodegenerative diseases of multiple etiologies. Volume 1 of this Special Issue has only been able to touch upon a few of the contributing factors regulating IOP and the causes behind death of RGCs and their axons in glaucoma. Clearly much more needs to be done to help rescue the compromised RGCs and their axons and to find suitable treatment options to permit preservation of vision in OHT/POAG and ocular normotensive patients. It is hoped that the review articles presented herein provide a fresh impetus for researchers to double their efforts in this regard. Such discovery research must continue as patients are waiting for these novel drugs and devices.