Prostanoid EP<sub>4</sub>Receptor Stimulation Produces Ocular Hypotension by a Mechanism That Does Not Appear to Involve Uveoscleral Outflow

Woodward, David F.; Nilsson, Stefan; Toris, Carol B.; Kharlamb, Alexander B.; Nieves, Amelia L.; Krauss, Achim H.-P.

doi:10.1167/iovs.08-3031

Cited by 38 publications

(35 citation statements)

References 37 publications

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“…Hori et al (2009) reported that local EP4 agonist treatment improved noise-induced hearing loss in guinea pigs. Finally, Woodward et al (2009) reported that an EP4 receptor agonist potently decreased intraocular pressure in laser-induced ocular hypertensive monkeys. EP4 could potentially be a new therapeutic target for antiglaucoma therapy.…”

Section: K Other Systemsmentioning

confidence: 99%

The Prostanoid EP4 Receptor and Its Signaling Pathway

Yokoyama

Iwatsubo²,

Umemura³

et al. 2013

Pharmacol Rev

222

257

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Section: K Other Systemsmentioning

confidence: 99%

The Prostanoid EP4 Receptor and Its Signaling Pathway

Yokoyama

Iwatsubo²,

Umemura³

et al. 2013

Pharmacol Rev

222

257

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“…Laser-induced ocular hypertension in monkeys was used, as previously described (Woodward et al, 2009). Briefly, female cynomolgus monkeys, weighing 2-4 kg, were trained to accept pneumatonometry, while conscious, in customdesigned restraining chairs.…”

Section: Methodsmentioning

confidence: 99%

“…To extend the pharmacological characterization of PGE 2 -glyceryl ester to an integrated living biologic system, we used the eye for convenient noninvasive study. Intraocular pressure was recorded in these experiments, since it is well-known to be influenced by the majority of prostanoid receptors (Hoyng and de Jong, 1987;Woodward et al, 1990Woodward et al, , 1994Woodward et al, , 2009Stjernschantz and Resul, 1992;Nilsson et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Prostaglandin E2-Glyceryl Ester: In Vivo Evidence for a Distinct Pharmacological Identity from Intraocular Pressure Studies

Woodward

Poloso

Wang

2016

Journal of Pharmacology and Experimental Therapeutics

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Prostaglandin E 2 (PGE 2 )-2-glyceryl ester is a cyclo-oxygenase 2 product of the endocannabinoid 2-arachidonyl glycerol. It is claimed as pharmacologically novel, but this is complicated by rapid and irreversible isomerization to the 1(3) ester. For ocular studies, enzymatic hydrolysis of the ester moiety creates an additional complication. PG-glyceryl esters were stabilized to isomerization and hydrolysis by replacing the noncarbonyl O with NH, to form the serinolamide and propanediolamide as stable analogs of PG-2-glyceryl and PG-2-1(3) glyceryl esters, respectively. Intraocular pressure was measured in conscious dogs and conscious laser-induced ocular hypertensive monkeys. Pharmacological studies involved stable transfectants for each of the human recombinant prostanoid receptors and the isolated feline iris for prostamide activity. PGE 2 -serinolamide and PGE 2 -propanediolamide were essentially inactive at all receptors except the EP 3 receptor (EC 50 , ∼500 nM). This obliged elucidation of EP 3 receptor involvement in the intraocular pressure response to these PGE 2 -glycyerl ester analogs. Since the EP 3 receptor agonists sulprostone and GR 63799 did not lower monkey intraocular pressure, a role for EP 3 receptors in mediating the effects of PGE 2 -serinolamide and PGE 2 -propanediolamide is not indicated. PGE 2 -glyceryl ester (0.01% and 0.1%) substantially lowered intraocular pressure in monkeys. PGE 2 -propanediolamide was more efficacious than PGE 2 -serinolamide in lowering intraocular pressure in monkey eyes, but both appeared equieffective in dog eyes. PGE 2 -serinolamide dose-dependently (0.01-0.1%) lowered intraocular pressure in both species, but PGF 2a -serinolamide was inactive. In conclusion, stable PGE 2 -glyceryl ester analogs lowered intraocular pressure. These findings are consistent with the presence of a PGE 2 -glyceryl ester-specific recognition site in the eye.

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“…However, the unique receptor profile for each analog may induce ECM modulation via different cascade pathways. One EP4 receptor agonist in particular has been shown to induce an increase in conventional outflow facility specifically [129]. Comparisons have been made between the effects of laser treatment and prostaglandins in SC monolayer permeability.…”

Section: Traditional Topical Medications In the Management Of Glaucomamentioning

confidence: 99%

“…Furthermore, selective EP 4 agonists have also been shown to be efficacious in treatment of POAG. Both SC and TM cells express EP 4 receptors, and hypertension-lowering effects are believed to be primarily localized to the conventional pathway [129,175]. EP 4 receptors alone induce expression of early growth response factor-1, mediated by extracellular signal-regulated kinases [176], while these kinases are also known to influence MMP expression [177].…”

Section: New Classes Of Drugmentioning

confidence: 99%

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

O’Callaghan

Cassidy

Humphries

2017

Expert Opinion on Therapeutic Targets

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Introduction:Ocular hypertension in open-angle glaucoma is caused by a reduced rate of removal of aqueous humour (AH) from the eye, with the majority of AH draining from the anterior chamber through the conventional outflow pathway, comprising the trabecular meshwork (TM) and Schlemm's Canal. Resistance to outflow is generated, in part, by the extracellular matrix (ECM) of the outflow tissues. Current pressure-lowering topical medications largely suppress AH production, or enhance its clearance through the unconventional pathway. However, therapies targeting the ECM of the conventional pathway in order to decrease intraocular pressure have become a recent focus of attention. Areas covered: We discuss the role of ECM of the TM in outflow homeostasis and its relevance as a target for glaucoma therapy, including progress in development of topical eye formulations, together with gene therapy approaches based on inducible, virally-mediated expression of matrix metalloproteinases to enhance aqueous outflow. Expert opinion: There remains a need for improved glaucoma medications that more specifically act upon sites causative to glaucoma pathogenesis. Emerging strategies targeting the ECM of the conventional outflow pathway, or associated components of the cytoskeleton of TM cells, involving new pharmacological formulations or genetically-based therapies, are promising avenues of future glaucoma treatment. ARTICLE HISTORY

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Prostanoid EP₄Receptor Stimulation Produces Ocular Hypotension by a Mechanism That Does Not Appear to Involve Uveoscleral Outflow

Abstract: The EP(4) receptor agonist 3,7-dithia PGE(1) is a highly efficacious IOP-lowering drug in monkeys. It has no effect on uveoscleral outflow but does increase total outflow facility, which accounts for a substantial proportion of the ocular hypotensive activity.

Cited by 38 publications

References 37 publications

The Prostanoid EP4 Receptor and Its Signaling Pathway

The Prostanoid EP4 Receptor and Its Signaling Pathway

Prostaglandin E2-Glyceryl Ester: In Vivo Evidence for a Distinct Pharmacological Identity from Intraocular Pressure Studies

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

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Prostanoid EP4Receptor Stimulation Produces Ocular Hypotension by a Mechanism That Does Not Appear to Involve Uveoscleral Outflow

Abstract: The EP(4) receptor agonist 3,7-dithia PGE(1) is a highly efficacious IOP-lowering drug in monkeys. It has no effect on uveoscleral outflow but does increase total outflow facility, which accounts for a substantial proportion of the ocular hypotensive activity.

Cited by 38 publications

References 37 publications

The Prostanoid EP4 Receptor and Its Signaling Pathway

The Prostanoid EP4 Receptor and Its Signaling Pathway

Prostaglandin E2-Glyceryl Ester: In Vivo Evidence for a Distinct Pharmacological Identity from Intraocular Pressure Studies

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

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Product

Resources

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Prostanoid EP₄Receptor Stimulation Produces Ocular Hypotension by a Mechanism That Does Not Appear to Involve Uveoscleral Outflow