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    • As indicated by the wide variety of pharmaceuticals for IOP

    2021-09-27

    As indicated by the wide variety of pharmaceuticals for IOP management (Table 1), each case of glaucoma is unique and requires a unique treatment regimen to effectively lower IOP. This often results in patients utilizing several medications at once and/or combining medications with surgical intervention. Over the long-term, the likelihood of preserving functional vision diminishes and the risk of significant blindness is considerably high. This is likely attributable to both poor patient compliance and the unilateral targeting of only one facet of the disease. The identification and targeting of other factors that contribute to glaucoma would be beneficial to patients, particularly those that do not respond well to IOP-dependent interventions. Neuroprotection for glaucoma could be an effective strategy, but studies aimed at protecting RGCs have thus far failed to demonstrate efficacy in clinical trials [30]. However, recent evidence supports the notion that targeting both neurobiological and IOP regulatory aspects of the disease may be more effective as a treatment strategy. For example, in a study comparing two adrenergic blockers timolol (beta-adrenergic) and brimonidine (alpha-adrenergic), brimonidine was more effective than timolol in stabilizing visual fields [31]. Both timolol and brimonidine reduce IOP by decreasing AqH production at the level of the non-pigmented ciliary epithelium [9,32] and display similar IOP-lowering efficacy [31]. However, brimonidine also has neuroprotective qualities, as demonstrated by its use in Alzheimer's disease and other cognitive impairments [33,34]. Thus, the identification of other pathways that could potentially target both IOP and neurodegeneration is intriguing and potentially beneficial.
    NO-GC pathway NO is a ubiquitous and endogenous signaling molecule. Since its discovery as an endothelium-derived relaxing factor (EDRF) in 1987 [35], NO has been implicated in a myriad of physiological processes, including smooth muscle relaxation and vasodilation [35,36], blood pressure regulation, anti-microbial defense and vascular JW 55 [37,38]. Nitric oxide synthase (NOS) is the enzyme that produces endogenous NO from l-arginine in a two-step oxidation process that also yields l-citrulline [[39], [40], [41]]. Molecular oxygen and reduced nicotinamide-adenine-dinucleotide phosphate (NADPH) are co-substrates (reviewed in [42]). There are three isoforms in mammals: neuronal NOS1 (nNOS), endothelial NOS3 (eNOS) and inducible NOS2 (iNOS) [43,44]. Under normal physiological conditions, NO is produced by the two constitutive, Ca2+/calmodulin-regulated isoforms of the enzyme (nNOS and eNOS), which generate relatively small amounts of NO (picomolar to nanomolar range) in response to a variety of stimuli, including elevated calcium and shear stress [45]. In pathological conditions (e.g. infection, inflammation or ischemia), there is induction of the third transcriptionally-regulated isoform of NOS (iNOS), which produces higher concentrations NO (micro to millimolar levels) over longer time periods [46]. The differential isoforms of NOS, paired with its widespread distribution in most tissues, allows for an array of diverse biological functions of NO. The classic NO pathway starts with the binding of a ligand, i.e. a hormone or first messenger, to its receptor that then induces production of NO by NOS. NO is a lipophilic molecule capable of traversing the phospholipid membranes of cells, where it has numerous targets, reacting typically via thiol groups or transition metal centers [[47], [48], [49], [50]]. A major target of NO is the enzyme soluble guanylate cyclase (GC-1 and GC-2, formerly known as sGCα1β1 and sGCα2β1 respectively), the only known receptor of NO [[51], [52], [53]]. The GC enzyme is a heme-containing heterodimeric protein, consisting of one α and one β subunit (Fig. 2) [52]. The GC-α1 and GC- β1 subunits that make up the GC-1 isoform are expressed in most cell types and tissues; however, two other subunits of GC, α2 and β2, have also been identified [54]. Although GC-1 is the most abundantly expressed form, other mixed heterodimer combinations of the protein have been identified, such as GC-2 (formerly sGCα2β1), which is expressed in the brain, placenta, spleen, and uterus [54,55]. This review will focus on GC-1, which converts guanosine triphosphate into the secondary messenger cGMP (Fig. 2) [[56], [57], [58]]. Upon NO binding, the activity of GC-1 increases more than 200-fold [59,60] producing high concentrations of cGMP that then modulate functions of numerous downstream enzymes, such as cyclic nucleotide phosphodiesterases (PDEs), cGMP-dependent protein kinases and cGMP-gated ion channels [61,62] (reviewed in [63]; Fig. 2). Downstream signaling cascades produce different biological effects depending on the location of NO release and the site of cGMP production.