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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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CXCR3 antagonism-induced lowering of intraocular pressure prevents retinal neurodegeneration and protects visual function in a rat model of ocular hypertension.(A,B) Ocular hypertension during 3 months is associated with a degradation in the visual function (A) as assessed by the duration of visual tracking during a 1-min optokinetic testing (spatial frequency, 0.5 cycle/degree), and with a decrease in retinal nerve fiber density (B) as measured in vivo by scanning light ophthalmoscopy. Ophthalmic treatment with CXCR3 antagonist significantly protects the visual function and prevents retinal nerve fiber loss (n = 10 each). (C) Ocular hypertension during one month is associated with an increase in retinal ganglion cell apoptosis (reported as the number of TUNEL-labeled cells normalized to the observed retinal layer length), which is reversed 15 days after the treatment with CXCR3 antagonist (n = 10 each). ** P<0.01 vs. normotensive eyes, §§ P<0.01 vs. untreated hypertensive eyes. Data in graphs are presented as means ± SEM.
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pone-0037873-g006: CXCR3 antagonism-induced lowering of intraocular pressure prevents retinal neurodegeneration and protects visual function in a rat model of ocular hypertension.(A,B) Ocular hypertension during 3 months is associated with a degradation in the visual function (A) as assessed by the duration of visual tracking during a 1-min optokinetic testing (spatial frequency, 0.5 cycle/degree), and with a decrease in retinal nerve fiber density (B) as measured in vivo by scanning light ophthalmoscopy. Ophthalmic treatment with CXCR3 antagonist significantly protects the visual function and prevents retinal nerve fiber loss (n = 10 each). (C) Ocular hypertension during one month is associated with an increase in retinal ganglion cell apoptosis (reported as the number of TUNEL-labeled cells normalized to the observed retinal layer length), which is reversed 15 days after the treatment with CXCR3 antagonist (n = 10 each). ** P<0.01 vs. normotensive eyes, §§ P<0.01 vs. untreated hypertensive eyes. Data in graphs are presented as means ± SEM.

Mentions: In parallel, OHT-related retinal degeneration and related visual degradation were studied. In our animal model, retinal nerve fiber density was significantly decreased in eyes with OHT compared to controls three months after the surgery as assessed in vivo by confocal scanning laser ophthalmoscopy (Fig. 6A). Eyes treated with selective CXCR3 antagonist presented higher nerve fiber density than untreated hypertensive eyes (Fig. 6A). Similarly, the visual function was better in NBI-74330-treated eyes than in untreated controls as assessed by optokinetic measurements (Fig. 6B). Ex vivo, NBI-74330-related reduction in IOP was associated with a decrease in retinal ganglion cell apoptosis as assessed by TUNEL-labeling (Fig. 6C).


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)

CXCR3 antagonism-induced lowering of intraocular pressure prevents retinal neurodegeneration and protects visual function in a rat model of ocular hypertension.(A,B) Ocular hypertension during 3 months is associated with a degradation in the visual function (A) as assessed by the duration of visual tracking during a 1-min optokinetic testing (spatial frequency, 0.5 cycle/degree), and with a decrease in retinal nerve fiber density (B) as measured in vivo by scanning light ophthalmoscopy. Ophthalmic treatment with CXCR3 antagonist significantly protects the visual function and prevents retinal nerve fiber loss (n = 10 each). (C) Ocular hypertension during one month is associated with an increase in retinal ganglion cell apoptosis (reported as the number of TUNEL-labeled cells normalized to the observed retinal layer length), which is reversed 15 days after the treatment with CXCR3 antagonist (n = 10 each). ** P<0.01 vs. normotensive eyes, §§ P<0.01 vs. untreated hypertensive eyes. Data in graphs are presented as means ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3366966&req=5

pone-0037873-g006: CXCR3 antagonism-induced lowering of intraocular pressure prevents retinal neurodegeneration and protects visual function in a rat model of ocular hypertension.(A,B) Ocular hypertension during 3 months is associated with a degradation in the visual function (A) as assessed by the duration of visual tracking during a 1-min optokinetic testing (spatial frequency, 0.5 cycle/degree), and with a decrease in retinal nerve fiber density (B) as measured in vivo by scanning light ophthalmoscopy. Ophthalmic treatment with CXCR3 antagonist significantly protects the visual function and prevents retinal nerve fiber loss (n = 10 each). (C) Ocular hypertension during one month is associated with an increase in retinal ganglion cell apoptosis (reported as the number of TUNEL-labeled cells normalized to the observed retinal layer length), which is reversed 15 days after the treatment with CXCR3 antagonist (n = 10 each). ** P<0.01 vs. normotensive eyes, §§ P<0.01 vs. untreated hypertensive eyes. Data in graphs are presented as means ± SEM.
Mentions: In parallel, OHT-related retinal degeneration and related visual degradation were studied. In our animal model, retinal nerve fiber density was significantly decreased in eyes with OHT compared to controls three months after the surgery as assessed in vivo by confocal scanning laser ophthalmoscopy (Fig. 6A). Eyes treated with selective CXCR3 antagonist presented higher nerve fiber density than untreated hypertensive eyes (Fig. 6A). Similarly, the visual function was better in NBI-74330-treated eyes than in untreated controls as assessed by optokinetic measurements (Fig. 6B). Ex vivo, NBI-74330-related reduction in IOP was associated with a decrease in retinal ganglion cell apoptosis as assessed by TUNEL-labeling (Fig. 6C).

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