Dataset Information

Trabodenoson, an Adenosine Mimetic With A1 Receptor Selectivity Lowers Intraocular Pressure by Increasing Conventional Outflow Facility in Mice.

ABSTRACT: To evaluate the relationship between the IOP-lowering effect of trabodenoson and the associated structural and functional changes in the trabecular meshwork (TM).Six independent cohorts of young and aged mice were exposed to three different topical once-a-day formulations of trabodenoson and eyes were compared to those treated with placebo drops. IOP was measured daily just before drug administration using rebound tonometry. Outflow facility was measured in enucleated eyes. Flow patterns and morphology of conventional outflow tissues were monitored using tracer beads and standard histology, respectively. In parallel, three-dimensional human TM tissue constructs (3D-HTM) were grown and used in experiments to test effect of trabodenoson on the expression of collagen IV, fibronectin, matrix metalloproteinase (MMP)-2 and MMP-14 plus MMP-2 activity.Topical administration of trabodenoson significantly lowered IOP on every day tested, up to 7 days. After 2 days of treatment, outflow facility increased by 26% in aged mice and 30% overall (young and aged mice), which was significantly different from vehicle (P < 0.05). Outflow facility was 15% higher than controls after 7 days of treatment (P = 0.07). While gross morphology was not affected by treatment, the intensity of tracer bead distribution increased by day 7 (P = 0.05). Parallel experiments in 3D-HTM showed that trabodenoson treatment significantly increased MMP-2 activity and MMP-14 abundance, while decreasing fibronectin and collagen IV expression.Trabodenoson alters ECM turnover by TM cells and increases conventional outflow facility, which accounts for its ability to lower IOP in young and aged mice.

SUBMITTER: Li G

PROVIDER: S-EPMC5774255 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Trabodenoson, an Adenosine Mimetic With A1 Receptor Selectivity Lowers Intraocular Pressure by Increasing Conventional Outflow Facility in Mice.

Li Guorong G Torrejon Karen Y KY Unser Andrea M AM Ahmed Feryan F Navarro Iris D ID Baumgartner Rudolf A RA Albers David S DS Stamer W Daniel WD

Investigative ophthalmology & visual science 20180101 1

<h4>Purpose</h4>To evaluate the relationship between the IOP-lowering effect of trabodenoson and the associated structural and functional changes in the trabecular meshwork (TM).<h4>Methods</h4>Six independent cohorts of young and aged mice were exposed to three different topical once-a-day formulations of trabodenoson and eyes were compared to those treated with placebo drops. IOP was measured daily just before drug administration using rebound tonometry. Outflow facility was measured in enucle ...[more]

PMID: 29346804

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Project description:BACKGROUND AND PURPOSE: Nitric oxide (NO) production and depression of neuromuscular transmission are closely related, but little is known about the role of L-citrulline, a co-product of NO biosynthesis, on neurotransmitter release. EXPERIMENTAL APPROACH: Muscle tension recordings and outflow experiments were performed on rat phrenic nerve-hemidiaphragm preparations stimulated electrically. KEY RESULTS: L-citrulline concentration-dependently inhibited evoked [(3)H]ACh release from motor nerve terminals and depressed nerve-evoked muscle contractions. The NO synthase (NOS) substrate, L-arginine, and the NO donor, 3-morpholinosydnonimine chloride (SIN-1), also inhibited [(3)H]ACh release with a potency order of SIN-1>L-arginine>L-citrulline. Co-application of L-citrulline and SIN-1 caused additive effects. NOS inactivation with N(omega)-nitro-L-arginine prevented L-arginine inhibition, but not that of L-citrulline. The NO scavenger, haemoglobin, abolished inhibition of [(3)H]ACh release caused by SIN-1, but not that caused by L-arginine. Inactivation of guanylyl cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) fully blocked SIN-1 inhibition, but only partially attenuated the effects of L-arginine. Reduction of extracellular adenosine accumulation with adenosine deaminase or with the nucleoside transport inhibitor, S-(p-nitrobenzyl)-6-thioinosine, attenuated the effects of L-arginine and L-citrulline, while not affecting inhibition by SIN-1. Similar results were obtained with the selective adenosine A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine. L-citrulline increased the resting extracellular concentration of adenosine, without changing that of the adenine nucleotides. CONCLUSIONS AND IMPLICATIONS: NOS catalyses the formation of two neuronally active products, NO and L-citrulline. While, NO may directly reduce transmitter release through stimulation of soluble guanylyl cyclase, the inhibitory action of L-citrulline may be indirect through increasing adenosine outflow and subsequently activating inhibitory A(1) receptors.

Dataset Information

Trabodenoson, an Adenosine Mimetic With A1 Receptor Selectivity Lowers Intraocular Pressure by Increasing Conventional Outflow Facility in Mice.

Publications

Trabodenoson, an Adenosine Mimetic With A1 Receptor Selectivity Lowers Intraocular Pressure by Increasing Conventional Outflow Facility in Mice.

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