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CXCR3 antagonism of SDF-1(5-67) restores trabecular function and prevents retinal neurodegeneration in a rat model of ocular hypertension.
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (6), pp. e37873. Date of Electronic Publication: 2012 Jun 04. - Publication Year :
- 2012
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Abstract
- 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.
- Subjects :
- Animals
Apoptosis drug effects
Caspase 3 metabolism
Cell Line
Cytoprotection drug effects
Disease Models, Animal
Enzyme Activation drug effects
Glaucoma complications
Glaucoma metabolism
Glaucoma pathology
Glaucoma physiopathology
Humans
Intraocular Pressure drug effects
Male
Rats
Rats, Long-Evans
Receptors, CXCR3 metabolism
Receptors, CXCR4 metabolism
Retinal Degeneration physiopathology
Stress, Physiological drug effects
Trabecular Meshwork drug effects
Trabecular Meshwork pathology
Vision, Ocular drug effects
Chemokine CXCL12 pharmacology
Ocular Hypertension complications
Ocular Hypertension physiopathology
Receptors, CXCR3 antagonists & inhibitors
Retinal Degeneration complications
Retinal Degeneration prevention & control
Trabecular Meshwork physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 22675496
- Full Text :
- https://doi.org/10.1371/journal.pone.0037873