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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.

Denoyer A, Godefroy D, Célérier I, Frugier J, Degardin J, Harrison JK, Brignole-Baudouin F, Picaud S, Baleux F, Sahel JA, Rostène W, Baudouin C - PLoS ONE (2012)

Bottom Line: Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed.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.

View Article: PubMed Central - PubMed

Affiliation: UPMC University Paris 6, Institut de la Vision, UMRS968, Paris, France. alexandre.denoyer@gmail.com

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.

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Ophthalmic administration of CXCR3 antagonist decreases intraocular pressure in a rat model of ocular hypertension.(A) A single administration of CXCR3 antagonist (NBI-74330, 1 µM, 100 µL) induces a transient decrease in intraocular pressure (n = 10 in each group). (B) When the antagonist is administrated twice, intraocular pressure remains low during 6 weeks (n = 10 each); the black arrow indicates the period of retinal and visual in vivo testing presented in Fig. 6A,B. (C) Dose-dependent effect of two administrations of CXCR3 antagonist on intraocular pressure as tested two weeks after the treatment (n = 5 each). * P<0.05, ** P<0.01. Data in graphs are presented as means ± SEM.
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pone-0037873-g004: Ophthalmic administration of CXCR3 antagonist decreases intraocular pressure in a rat model of ocular hypertension.(A) A single administration of CXCR3 antagonist (NBI-74330, 1 µM, 100 µL) induces a transient decrease in intraocular pressure (n = 10 in each group). (B) When the antagonist is administrated twice, intraocular pressure remains low during 6 weeks (n = 10 each); the black arrow indicates the period of retinal and visual in vivo testing presented in Fig. 6A,B. (C) Dose-dependent effect of two administrations of CXCR3 antagonist on intraocular pressure as tested two weeks after the treatment (n = 5 each). * P<0.05, ** P<0.01. Data in graphs are presented as means ± SEM.

Mentions: In order to extent our in vitro data, we tested in vivo whether CXCR3 and/or CXCR4 were implicated in the regulation of IOP by using highly selective non-peptide antagonists of both chemokine receptors in a rat model of OHT and related retinal degeneration, which was induced by episcleral vein cauterization [29]. AMD-3100 [31] (1 µM, 100 µL) or NBI-74330 [29], [30] (1 µM, 100 µL), selective antagonists for CXCR4 and CXCR3 respectively, were administrated in the subconjunctival space of rat eyes. A single administration of NBI-74330 induced a decrease in IOP 4 days after the treatment, reaching the normal IOP values observed in normotensive control eyes (Fig. 4A). This decrease in IOP was transient since IOP returned to elevated values of untreated eyes after 6 days. When a second administration was given at the time of maximal decrease, IOP remained low during a period of 6 weeks (Fig. 4B). NBI-74330 reduced IOP in a dose-dependent manner (Fig. 4C). In contrast, subconjunctival administration of a CXCR4 selective antagonist did not influence IOP in eyes with OHT (Fig. S2). In control eyes, the antagonists had no effect. In parallel, CXCL12 and SDF-1(5-67) were tested in normal rat eyes for their ability to modify IOP. CXCL12 ocular injections had no significant effect on IOP, whereas two injections of SDF-1(5-67) significantly increased IOP that remained elevated for 3 days (Fig. S3).


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

Denoyer A, Godefroy D, Célérier I, Frugier J, Degardin J, Harrison JK, Brignole-Baudouin F, Picaud S, Baleux F, Sahel JA, Rostène W, Baudouin C - PLoS ONE (2012)

Ophthalmic administration of CXCR3 antagonist decreases intraocular pressure in a rat model of ocular hypertension.(A) A single administration of CXCR3 antagonist (NBI-74330, 1 µM, 100 µL) induces a transient decrease in intraocular pressure (n = 10 in each group). (B) When the antagonist is administrated twice, intraocular pressure remains low during 6 weeks (n = 10 each); the black arrow indicates the period of retinal and visual in vivo testing presented in Fig. 6A,B. (C) Dose-dependent effect of two administrations of CXCR3 antagonist on intraocular pressure as tested two weeks after the treatment (n = 5 each). * P<0.05, ** P<0.01. Data in graphs are presented as means ± SEM.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3366966&req=5

pone-0037873-g004: Ophthalmic administration of CXCR3 antagonist decreases intraocular pressure in a rat model of ocular hypertension.(A) A single administration of CXCR3 antagonist (NBI-74330, 1 µM, 100 µL) induces a transient decrease in intraocular pressure (n = 10 in each group). (B) When the antagonist is administrated twice, intraocular pressure remains low during 6 weeks (n = 10 each); the black arrow indicates the period of retinal and visual in vivo testing presented in Fig. 6A,B. (C) Dose-dependent effect of two administrations of CXCR3 antagonist on intraocular pressure as tested two weeks after the treatment (n = 5 each). * P<0.05, ** P<0.01. Data in graphs are presented as means ± SEM.
Mentions: In order to extent our in vitro data, we tested in vivo whether CXCR3 and/or CXCR4 were implicated in the regulation of IOP by using highly selective non-peptide antagonists of both chemokine receptors in a rat model of OHT and related retinal degeneration, which was induced by episcleral vein cauterization [29]. AMD-3100 [31] (1 µM, 100 µL) or NBI-74330 [29], [30] (1 µM, 100 µL), selective antagonists for CXCR4 and CXCR3 respectively, were administrated in the subconjunctival space of rat eyes. A single administration of NBI-74330 induced a decrease in IOP 4 days after the treatment, reaching the normal IOP values observed in normotensive control eyes (Fig. 4A). This decrease in IOP was transient since IOP returned to elevated values of untreated eyes after 6 days. When a second administration was given at the time of maximal decrease, IOP remained low during a period of 6 weeks (Fig. 4B). NBI-74330 reduced IOP in a dose-dependent manner (Fig. 4C). In contrast, subconjunctival administration of a CXCR4 selective antagonist did not influence IOP in eyes with OHT (Fig. S2). In control eyes, the antagonists had no effect. In parallel, CXCL12 and SDF-1(5-67) were tested in normal rat eyes for their ability to modify IOP. CXCL12 ocular injections had no significant effect on IOP, whereas two injections of SDF-1(5-67) significantly increased IOP that remained elevated for 3 days (Fig. S3).

Bottom Line: Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed.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.

View Article: PubMed Central - PubMed

Affiliation: UPMC University Paris 6, Institut de la Vision, UMRS968, Paris, France. alexandre.denoyer@gmail.com

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.

Show MeSH
Related in: MedlinePlus