CXCR3 antagonism of SDF-1(5-67) restores trabecular function and prevents retinal neurodegeneration in a rat model of ocular hypertension

Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatme...

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Bibliographic Details
Published in:PloS one 2012-06, Vol.7 (6), p.e37873
Main Authors: Denoyer, Alexandre, Godefroy, David, Célérier, Isabelle, Frugier, Julie, Degardin, Julie, Harrison, Jeffrey K, Brignole-Baudouin, Francoise, Picaud, Serge, Baleux, Francoise, Sahel, José A, Rostène, William, Baudouin, Christophe
Format: Article
Language:English
Subjects:
Animals
Antagonism
Apoptosis
Apoptosis - drug effects
Autophagy
Biology
Blindness
Cadmium
Caspase
Caspase 3
Caspase 3 - metabolism
Cell Line
Chemokine CXCL12
Chemokine CXCL12 - pharmacology
Chemokines
CXCL12 protein
CXCR3 protein
CXCR4 protein
Cytoprotection
Cytoprotection - drug effects
Data processing
Degeneration
Disease Models, Animal
Drug therapy
Enzyme Activation
Enzyme Activation - drug effects
Extracellular matrix
Glaucoma
Glaucoma - complications
Glaucoma - metabolism
Glaucoma - pathology
Glaucoma - physiopathology
Health aspects
Humans
Hypertension
Infections
Intraocular Pressure
Intraocular Pressure - drug effects
Life Sciences
Male
Medicine
Metallography
Neurodegeneration
Neuropathy
Ocular Hypertension
Ocular Hypertension - complications
Ocular Hypertension - physiopathology
Pathology
Peptides
Proteases
Proteolysis
Rats
Rats, Long-Evans
Receptors
Receptors, CXCR3
Receptors, CXCR3 - antagonists & inhibitors
Receptors, CXCR3 - metabolism
Receptors, CXCR4
Receptors, CXCR4 - metabolism
Restoration
Retina
Retinal Degeneration
Retinal Degeneration - complications
Retinal Degeneration - physiopathology
Retinal Degeneration - prevention & control
Rodents
SDF-1 protein
Stress, Physiological
Stress, Physiological - drug effects
Trabecular Meshwork
Trabecular Meshwork - drug effects
Trabecular Meshwork - pathology
Trabecular Meshwork - physiopathology
Transforming growth factor- beta
Transforming growth factors
Tumor necrosis factor- alpha
Tumor necrosis factor-α
Ultrasonic imaging
Vision, Ocular
Vision, Ocular - drug effects
Visual effects
Visual perception
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Summary:Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0037873