New Therapeutic Targets for Intraocular Pressure Lowering

Rocha‐Sousa, Amândio; Rodrigues-Araújo, J.; Gouveia, Petra; Breda, João Barbosa; Azevedo-Pinto, Sara; Pereira-Silva, P; Leite‐Moreira, A.F.

doi:10.1155/2013/261386

Cited by 35 publications

(21 citation statements)

References 124 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Administration of NO or its overexpression produces enzyme endothelial nitric oxide synthase (eNOS), resulting in increased outflow facility and/or decreased IOP (Dismuke et al, ; Stamer et al, ). NO binds the maxi‐K channels and leads to relaxation of the trabecular meshwork, presumably by changing the conformation of cytoskeletal proteins (Rocha‐Sousa et al, ). Similarly, platelet‐derived growth factor (PDGF) is able to induce cytoskeletal changes by activating the RAc1 pathway (a member of the small GTPasase family) leading to enhanced outflow facility (Syriani et al, ).…”

Section: Trabecular Meshwork Motilitymentioning

confidence: 99%

The Outflow Pathway: A Tissue With Morphological and Functional Unity

Saccà

Gandolfi

Bagnis

et al. 2016

Journal Cellular Physiology

View full text Add to dashboard Cite

The trabecular meshwork (TM) plays an important role in high-tension glaucomas. Indeed, the TM is a true organ, through which the aqueous humor flows from the anterior chamber to Schlemm's canal (SC). Until recently, the TM, which is constituted by endothelial-like cells, was described as a kind of passive filter. In reality, it is much more. The cells delineating the structures of the collagen framework of the TM are endowed with a cytoskeleton, and are thus able to change their shape. These cells also have the ability to secrete the extracellular matrix, which expresses proteins and cytokines, and are capable of phagocytosis and autophagy. The cytoskeleton is attached to the nuclear membrane and can, in millionths of a second, send signals to the nucleus in order to alter the expression of genes in an attempt to adapt to biomechanical insult. Oxidative stress, as happens in aging, has a deleterious effect on the TM, leading eventually to cell decay, tissue malfunction, subclinical inflammation, changes in the extracellular matrix and cytoskeleton, altered motility, reduced outflow facility, and (ultimately) increased IOP. TM failure is the most relevant factor in the cascade of events triggering apoptosis in the inner retinal layers, including ganglion cells. J. Cell. Physiol. 231: 1876-1893, 2016. © 2016 Wiley Periodicals, Inc.

show abstract

Section: Trabecular Meshwork Motilitymentioning

confidence: 99%

The Outflow Pathway: A Tissue With Morphological and Functional Unity

Saccà

Gandolfi

Bagnis

et al. 2016

Journal Cellular Physiology

View full text Add to dashboard Cite

show abstract

“…[10][11][12] To date, a specific mechanism for this effect has not been elucidated. 13,14 Cannabinoids have two different receptor subtypes, CB1 and CB2. Based on the expression of CB1 in both structures of the eye where aqueous humor was produced and removed, it was proposed that cannabinoids induced IOP reduction via CB1 receptor activation.…”

Section: Discussionmentioning

confidence: 99%

Bimatoprost Increases Mechanosensitivity of Trigeminal Ganglion Neurons Innervating the Inner Walls of Rat Anterior Chambers via Activation of TRPA1

Ling

Meng

et al. 2016

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

Citation: Ling Y, Hu Z, Meng Q, Fang P, Liu H. Bimatoprost increases mechanosensitivity of trigeminal ganglion neurons innervating the inner walls of rat anterior chambers via activation of TRPA1. Invest Ophthalmol Vis Sci. 2016;57:567-576. DOI:10.1167/ iovs.15-18108 PURPOSE. Our previous study found that some trigeminal ganglion (TG) nerve endings in the inner walls of rat anterior chambers were mechanosensitive, and transient receptor potential ankyrin 1 (TRPA1) was an essential mechanosensitive channel in the membrane. To address the effect of bimatoprost on the mechanosensitive TG nerve endings in the inner walls of rat anterior chambers, we investigated its effect on their cell bodies in vitro.METHODS. Rat TG neurons innervating the inner walls of the anterior chambers were labeled by anterior chamber injection of 1,1 0 -dilinoleyl-3,3,3 0 ,3 0 -tetramethylindocarbocyanine, 4-chlorobenzenesulfonate (FAST DiI). Calcium imaging and whole cell patch clamp were used on neuronal cell bodies to detect the activation effect of TRPA1 channels. Whole cell patch clamp was performed to record the currents induced by drugs and mechanical stimulation.Mechanical stimulation was applied to the neurons by buffer ejection. RESULTS. Bimatoprost mimicked the effect of TRPA1 agonists, allyl isothiocyanate (AITC), and (R)-(þ)- CONCLUSIONS.Our results indicate that bimatoprost is a novel agonist of TRPA1, and it can enhance mechanosensitivity of TG nerve endings in the inner walls of anterior eye chambers via TRPA1 activation in rats.Keywords: intraocular pressure, mechanosensitive channel, trigeminal ganglion, transient receptor potential ankyrin 1, bimatoprost L atanoprost, travoprost, and bimatoprost are three efficacious prostanoid analogs used for the treatment of glaucoma. Their effects on aqueous humor outflow are similar. Despite the well-established efficacy of these drugs on intraocular pressure (IOP), the mechanism underlying the hypotensive effect is not fully understood. Latanoprost and travoprost are prodrugs of prostaglandin (PG) FP receptor agonists. A well-studied mechanism for their enhancement of aqueous outflow is the regulation of matrix metalloproteinases and remodeling of extracellular matrix via FP receptor activation.1 However, experimental and clinical evidence suggests that bimatoprost and prostanoid FP receptor agonists stimulate different receptor populations.2-4 Studies performed on a wide array of receptors, ion channels, and transporters have demonstrated that bimatoprost does not meaningfully interact with adrenergic, cholinergic, cannabinoid, dopaminergic, or any of the known prostaglandin receptors, indicating that these receptors are not involved in the mediation of bimatoprost-induced responses.2-4 It has been shown that 17-phenyl prostaglandin F2alpha (PGF2a), an acid hydrolysis product of bimatoprost, is found in the aqueous humor after topical application of bimatoprost in humans.5 Based on the finding that 17-phenyl PGF2a is a potent FP prostanoid receptor agonist, it was proposed t...

show abstract

“…212 These include other targets to (a) increase ONH blood flow 213 , (b) increase TM outflow via ECM remodeling or altering TM cell contractility, (c) increase uveoscleral outflow, and/or (d) decrease AH production. Here we highlight just a few examples of such targets, others are listed in Table 4.…”

Section: Selected Promising New Directions and Emerging Targetsmentioning

confidence: 99%

Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions

Donegan

Lieberman

2015

J. Med. Chem.

View full text Add to dashboard Cite

Glaucoma, a heterogeneous ocular disorder affecting ~60 million people worldwide, is characterized by painless neurodegeneration of retinal ganglion cells (RGCs), resulting in irreversible vision loss. Available therapies, which decrease the common causal risk factor of elevated intraocular pressure, delay, but cannot prevent, RGC death and blindness. Notably, it is changes in the anterior segment of the eye, particularly in the drainage of aqueous humor fluid, which are believed to bring about changes in pressure. Thus, it is primarily this region whose properties are manipulated in current and emerging therapies for glaucoma. Here, we focus on the challenges associated with developing treatments, review the available experimental methods to evaluate the therapeutic potential of new drugs, describe the development and evaluation of emerging Rho-kinase inhibitors and adenosine receptor ligands that offer the potential to improve aqueous humor outflow and protect RGCs simultaneously, and present new targets and approaches on the horizon.

show abstract

New Therapeutic Targets for Intraocular Pressure Lowering

Cited by 35 publications

References 124 publications

The Outflow Pathway: A Tissue With Morphological and Functional Unity

The Outflow Pathway: A Tissue With Morphological and Functional Unity

Bimatoprost Increases Mechanosensitivity of Trigeminal Ganglion Neurons Innervating the Inner Walls of Rat Anterior Chambers via Activation of TRPA1

Discovery of Molecular Therapeutics for Glaucoma: Challenges, Successes, and Promising Directions

Contact Info

Product

Resources

About