cyclic-gmp and Glaucoma

Glaucoma is a progressive age-related disease of the visual system and the leading cause of irreversible blindness worldwide. Currently, intraocular pressure (IOP) is the only modifiable risk factor for the disease, but even as IOP is lowered, the pathology of the disease often progresses. Hence, effective clinical targets for the treatment of glaucoma remain elusive. Glaucoma shares comorbidities with a multitude of vascular diseases, and evidence in humans and animal models demonstrates an association between vascular dysfunction of the retina and glaucoma pathology. Integral to the survival of retinal ganglion cells (RGCs) is functional neurovascular coupling (NVC), providing RGCs with metabolic support in response to neuronal activity. NVC is mediated by cells of the neurovascular unit (NVU), which include vascular cells, glial cells, and neurons. Nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling is a prime mediator of NVC between endothelial cells and neurons, but emerging evidence suggests that cGMP signaling is also important in the physiology of other cells of the NVU. NO-cGMP signaling has been implicated in glaucomatous neurodegeneration in humans and mice. In this review, we explore the role of cGMP signaling in the different cell types of the NVU and investigate the potential links between cGMP signaling, breakdown of neurovascular function, and glaucoma pathology.

Topics: Animals; Cyclic GMP; Endothelial Cells; Glaucoma; Humans; Intraocular Pressure; Mice; Retinal Ganglion Cells

Topics: Aqueous Humor; Calcium; Cataract; Cornea; Cyclic GMP; Eye; Glaucoma; Intraocular Pressure; Lens, Crystalline; Ocular Physiological Phenomena; Optics and Photonics; Photoreceptor Cells; Pigment Epithelium of Eye; Retina; Retinal Detachment; Retinal Pigments; Rod Cell Outer Segment

The nitric oxide - guanylyl cyclase-1 - cyclic guanylate monophosphate (NO-GC-1-cGMP) pathway has emerged as a potential pathogenic mechanism for glaucoma, a common intraocular pressure (IOP)-related optic neuropathy characterized by the degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve. NO activates GC-1 to increase cGMP levels, which are lowered by cGMP-specific phosphodiesterase (PDE) activity. This pathway appears to play a role in both the regulation of IOP, where reduced cGMP levels in mice leads to elevated IOP and subsequent RGC degeneration. Here, we investigated whether potentiation of cGMP signaling could protect RGCs from glaucomatous degeneration. We administered the PDE5 inhibitor tadalafil orally (10 mg/kg/day) in murine models of two forms of glaucoma - primary open angle glaucoma (POAG; GC-1

Topics: Animals; Apoptosis; Cells, Cultured; Cyclic GMP; Disease Models, Animal; Female; Glaucoma; Guanylate Cyclase; Mice, Knockout; Phosphodiesterase 5 Inhibitors; Rats, Sprague-Dawley; Retinal Degeneration; Retinal Ganglion Cells; Signal Transduction; Tadalafil

Soluble guanylate cyclase (sGC), the endogenous receptor for nitric oxide (NO), has been implicated in several diseases associated with oxidative stress. In a pathological oxidative environment, the heme group of sGC can be oxidized becoming unresponsive to NO leading to a loss in the ability to catalyze the production of cGMP. Recently a dysfunctional sGC/NO/cGMP pathway has been implicated in contributing to elevated intraocular pressure associated with glaucoma. Herein we describe the discovery of molecules specifically designed for topical ocular administration, which can activate oxidized sGC restoring the ability to catalyze the production of cGMP. These efforts culminated in the identification of compound (+)-23, which robustly lowers intraocular pressure in a cynomolgus model of elevated intraocular pressure over 24 h after a single topical ocular drop and has been selected for clinical evaluation.

Topics: Administration, Ophthalmic; Administration, Topical; Animals; CHO Cells; Cricetinae; Cricetulus; Cyclic GMP; Drug Discovery; Enzyme Activators; Glaucoma; Humans; Intraocular Pressure; Macaca fascicularis; Ophthalmic Solutions; Oxidation-Reduction; Rabbits; Soluble Guanylyl Cyclase

The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate.. Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354.. sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8- to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted.. MGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOP-lowering drugs in glaucoma patients could be further determined in clinical studies.

Topics: Administration, Ophthalmic; Animals; Antihypertensive Agents; Cells, Cultured; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Activators; Glaucoma; Humans; Immunohistochemistry; Intraocular Pressure; Macaca fascicularis; Ocular Hypotension; Ophthalmic Solutions; Piperidines; Pyrazoles; Pyridines; Rabbits; Soluble Guanylyl Cyclase; Trabecular Meshwork

The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Aqueous Humor; Cell Line; Ciliary Body; Cyclic GMP; Dinoprost; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Female; Glaucoma; Guanylate Cyclase; Intraocular Pressure; Iris; Latanoprost; Macaca fascicularis; Male; Nitric Oxide; Nitric Oxide Donors; Ocular Hypertension; Prostaglandins F, Synthetic; Rabbits; Rats; Tonometry, Ocular

Nitric oxide (NO) is involved in a variety of physiological processes including ocular aqueous humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compound, NCX 125, comprising latanoprost acid and NO-donating moieties.. NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma.. NCX 125 elicited cGMP formation (EC(50) = 3.8 + or - 1.0 microM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC(50) = 55 + or - 11 microM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Delta(max) = -10.6 + or - 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Delta(max)= -6.7 + or - 1.2 mm Hg; 0.039% NCX 125, Delta(max) = -9.1 + or - 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Delta(max) = -11.9 + or - 3.7 mm Hg, 0.13% NCX 125, Delta(max) = -16.7 + or - 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues.. NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Ciliary Body; Cyclic GMP; Disease Models, Animal; Dogs; Female; Glaucoma; Intraocular Pressure; Iris; Macaca fascicularis; Macrophages; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Ocular Hypertension; Ophthalmic Solutions; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rabbits; Tumor Cells, Cultured

To study the role of the L-arginine-nitric oxide (NO) pathway in aqueous humour dynamics by measuring nitrate, nitrite and cyclic (cGMP) levels in guanosine 3',5'-monophosphate the aqueous humour of glaucomatous and nonglaucomatous cataract patients.. The study involved 38 glaucoma patients undergoing unilateral cataract surgery in the glaucomatous eye and 38 cataract control patients matched for sex, age, smoking habits and organic nitrate medication. All subjects underwent ophthalmic examination, and blood pressure was measured preoperatively. Nitrite, nitrate and cGMP levels were measured in aqueous humour and serum.. The NOx (nitrite + nitrate), nitrite and cGMP concentrations in the aqueous humour were slightly higher in the glaucoma patients than in the control patients, but the differences did not reach statistical significance. The levels of cGMP in serum were higher in the glaucoma patients (P = 0.053). The subgroup of glaucoma patients with pseudoexfoliation had lower NOx and nitrite values in the aqueous humour (P = 0.046 and P = 0.345, respectively) than the matched controls, while cGMP levels were higher (P = 0.043). Levels of NOx and nitrite in the aqueous humour were higher in patients using oral nitroglycerin (P = 0.062 and P = 0.042, respectively) than in patients without this medication. Blood pressure was higher in the glaucoma patients, with a mean of 165/89 mmHg as compared to 153/81 mmHg in the controls (P-values 0.071/0.008).. No differences in NO metabolites were found between glaucoma and control patients. However, any real changes may have been disguised by optimal medication of glaucoma. Low NOx and high cGMP levels in the aqueous humour of pseudoexfoliation patients warrant further evaluation in a larger study.

Topics: Aged; Aqueous Humor; Arginine; Biomarkers; Blood Pressure; Cataract; Cyclic GMP; Female; Glaucoma; Humans; Intraocular Pressure; Male; Nitrates; Nitric Oxide; Nitrites; Prospective Studies; Signal Transduction

cAMP and cGMP contents were studied in various eye tissues of rabbits with experimental glaucoma induced by chronic intravenous adrenaline administration. Cyclic nucleotide level was measured in the retina, choroid, iris and ciliary body. An increase in the tissue cAMP level was found especially in the iris and ciliary body. An increase in tissue cAMP content is explained by an enhanced beta-adrenergic regulation in the eyes of rabbits with experimental glaucoma. No consistent changes were found in cGMP content in eye tissues.

Topics: Animals; Choroid; Ciliary Body; Cyclic AMP; Cyclic GMP; Epinephrine; Eye; Glaucoma; Iris; Rabbits; Receptors, Adrenergic, beta; Retina