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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 restores trabecular filtrating function and protects trabecular cells from apoptosis in a rat model of ocular hypertension.(A) Aqueous humor outflow impairment in hypertensive eyes is counteracted by treatment with CXCR3 antagonist as measured in vivo by fluorophotometry (n = 10 each). (B,C,D) Trabecular filtrating function is restored by treatment with CXCR3 antagonist as assessed by trabecular trapping of fluorescent microspheres (red), and quantitatively measured as percent of effective filtration length (PEFL), which is more important in treated eyes (B) than in untreated hypertensive eyes (C) (n = 10 each). (E,F,G) Density of apoptotic trabecular cells is lower in eyes treated with the CXCR3 antagonist (E) than in untreated hypertensive eyes (F), as assessed by TUNEL (green) and DAPI (blue) nuclear staining (n = 10 each). ** P<0.01. (scale bar, 50 µm). Data in bar graphs are presented as means ± SEM.
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pone-0037873-g005: Ophthalmic administration of CXCR3 antagonist restores trabecular filtrating function and protects trabecular cells from apoptosis in a rat model of ocular hypertension.(A) Aqueous humor outflow impairment in hypertensive eyes is counteracted by treatment with CXCR3 antagonist as measured in vivo by fluorophotometry (n = 10 each). (B,C,D) Trabecular filtrating function is restored by treatment with CXCR3 antagonist as assessed by trabecular trapping of fluorescent microspheres (red), and quantitatively measured as percent of effective filtration length (PEFL), which is more important in treated eyes (B) than in untreated hypertensive eyes (C) (n = 10 each). (E,F,G) Density of apoptotic trabecular cells is lower in eyes treated with the CXCR3 antagonist (E) than in untreated hypertensive eyes (F), as assessed by TUNEL (green) and DAPI (blue) nuclear staining (n = 10 each). ** P<0.01. (scale bar, 50 µm). Data in bar graphs are presented as means ± SEM.

Mentions: Investigations were conducted in the anterior segment of the eye in order to study mechanisms involved in the NBI-74330-related decrease in IOP. In our animal model, we observed a decrease in AH outflow together with a decrease in the TM filtrating surface in hypertensive eyes compared to normotensive controls, one month after the surgical procedure (Fig. 5A,B,C,D). AH outflow impairment was significantly counteracted by treatment with NBI-74330 (Fig. 5A). Furthermore, trabecular filtrating surface was also significantly improved by the selective CXCR3 antagonist (Fig. 5B,C,D). TC apoptosis was significantly detected in hypertensive eyes as compared to normotensive controls (Fig. 5E,F,G). In hypertensive eyes, apoptosis was significantly decreased by NBI-74330 as compared to untreated eyes. There was no inflammatory cell infiltration in the TM whatever the group as revealed by a lack of either anti-CD45 or anti-CD11b reactive cells. These data together suggested that blocking CXCR3 may lower OHT by restoring the trabecular filtrating function and protecting directly TCs from apoptosis.


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 restores trabecular filtrating function and protects trabecular cells from apoptosis in a rat model of ocular hypertension.(A) Aqueous humor outflow impairment in hypertensive eyes is counteracted by treatment with CXCR3 antagonist as measured in vivo by fluorophotometry (n = 10 each). (B,C,D) Trabecular filtrating function is restored by treatment with CXCR3 antagonist as assessed by trabecular trapping of fluorescent microspheres (red), and quantitatively measured as percent of effective filtration length (PEFL), which is more important in treated eyes (B) than in untreated hypertensive eyes (C) (n = 10 each). (E,F,G) Density of apoptotic trabecular cells is lower in eyes treated with the CXCR3 antagonist (E) than in untreated hypertensive eyes (F), as assessed by TUNEL (green) and DAPI (blue) nuclear staining (n = 10 each). ** P<0.01. (scale bar, 50 µm). Data in bar graphs are presented as means ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0037873-g005: Ophthalmic administration of CXCR3 antagonist restores trabecular filtrating function and protects trabecular cells from apoptosis in a rat model of ocular hypertension.(A) Aqueous humor outflow impairment in hypertensive eyes is counteracted by treatment with CXCR3 antagonist as measured in vivo by fluorophotometry (n = 10 each). (B,C,D) Trabecular filtrating function is restored by treatment with CXCR3 antagonist as assessed by trabecular trapping of fluorescent microspheres (red), and quantitatively measured as percent of effective filtration length (PEFL), which is more important in treated eyes (B) than in untreated hypertensive eyes (C) (n = 10 each). (E,F,G) Density of apoptotic trabecular cells is lower in eyes treated with the CXCR3 antagonist (E) than in untreated hypertensive eyes (F), as assessed by TUNEL (green) and DAPI (blue) nuclear staining (n = 10 each). ** P<0.01. (scale bar, 50 µm). Data in bar graphs are presented as means ± SEM.
Mentions: Investigations were conducted in the anterior segment of the eye in order to study mechanisms involved in the NBI-74330-related decrease in IOP. In our animal model, we observed a decrease in AH outflow together with a decrease in the TM filtrating surface in hypertensive eyes compared to normotensive controls, one month after the surgical procedure (Fig. 5A,B,C,D). AH outflow impairment was significantly counteracted by treatment with NBI-74330 (Fig. 5A). Furthermore, trabecular filtrating surface was also significantly improved by the selective CXCR3 antagonist (Fig. 5B,C,D). TC apoptosis was significantly detected in hypertensive eyes as compared to normotensive controls (Fig. 5E,F,G). In hypertensive eyes, apoptosis was significantly decreased by NBI-74330 as compared to untreated eyes. There was no inflammatory cell infiltration in the TM whatever the group as revealed by a lack of either anti-CD45 or anti-CD11b reactive cells. These data together suggested that blocking CXCR3 may lower OHT by restoring the trabecular filtrating function and protecting directly TCs from apoptosis.

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