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

• 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
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0037873

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.