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Glycosaminoglycan analogs as a novel anti-inflammatory strategy.

Severin IC, Soares A, Hantson J, Teixeira M, Sachs D, Valognes D, Scheer A, Schwarz MK, Wells TN, Proudfoot AE, Shaw J - Front Immunol (2012)

Bottom Line: In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation.However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment.In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.

View Article: PubMed Central - PubMed

Affiliation: Merck Serono Geneva Research Centre Geneva, Switzerland.

ABSTRACT
Heparin, a glycosaminoglycan (GAG), has both anti-inflammatory and anti-coagulant properties. The clinical use of heparin against inflammation, however, has been limited by concerns about increased bleeding. While the anti-coagulant activity of heparin is well understood, its anti-inflammatory properties are less so. Heparin is known to bind to certain cytokines, including chemokines, small proteins which mediate inflammation through their control of leukocyte migration and activation. Molecules which can interrupt the chemokine-GAG interaction without inhibiting coagulation could therefore, represent a new class of anti-inflammatory agents. In the present study, two approaches were undertaken, both focusing on the heparin-chemokine relationship. In the first, a structure based strategy was used: after an initial screening of potential small molecule binders using protein NMR on a target chemokine, binding molecules were optimized through structure-based design. In the second approach, commercially available short oligosaccharides were polysulfated. In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation. However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment. In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.

No MeSH data available.


Related in: MedlinePlus

Inhibition of delayed-type hypersensitivity. Immunization was performed by s.c. administration of SRBC, followed by a challenge in the hindpaw 5 days later. The persulfated oligosaccharides (10 mg/kg) were administered 30 min prior and 8 h after the challenge. Dexamethasone was used as a positive control, and paw thickness was measured 21 h following the challenge. The statistical differences vs. the control group (mice challenged with SRBC and treated with vehicle for the compounds 0.02% BSA diluted in PBS) are shown whenever present and indicated by *P <0.05>; ***P < 0.001.
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Figure 5: Inhibition of delayed-type hypersensitivity. Immunization was performed by s.c. administration of SRBC, followed by a challenge in the hindpaw 5 days later. The persulfated oligosaccharides (10 mg/kg) were administered 30 min prior and 8 h after the challenge. Dexamethasone was used as a positive control, and paw thickness was measured 21 h following the challenge. The statistical differences vs. the control group (mice challenged with SRBC and treated with vehicle for the compounds 0.02% BSA diluted in PBS) are shown whenever present and indicated by *P <0.05>; ***P < 0.001.

Mentions: Despite the fact that the peritoneal recruitment assay led to enhanced recruitment, we tested the anti-inflammatory potential of the sulfated GAG analogs in another model, delayed-type hypersensitivity. Initial experiments were performed in order to define the optimal dose and the regimen for the administration of MHxS. A dose-response experiment using 0.1, 1, and 10 mg/kg (dosing at −30 min and at +8 h post-challenge) was performed and statistically significant inhibitions were shown only for the highest dose (data not shown). In a subsequent experiment we tested whether we could alter the efficacy of MHxS in this model by varying the frequency of administrations while keeping the same dose of 10 mg/kg. We concluded that while the pre-administration of MHxS at −30 min was important for the observed effect, the administration of a pre-treatment dose 24 h before challenge on top of the dosings performed at −30 min and at +8 h did not further improve the inhibition in paw thickness-induced by MHxS. Finally, a head to head comparison of the efficacy of NisS, StachS, and MHxS was performed at the best conditions defined in earlier experiments, i.e., fixed dose of 10 mg/kg with compounds being administered at −30 min and +8 h post-challenge. These results are shown in Figure 5, where paw swelling was inhibited by treatment with NisS, StachS, and MHxS by an order of 20, 41, and 39% respectively in comparison to 47% for dexamethasone.


Glycosaminoglycan analogs as a novel anti-inflammatory strategy.

Severin IC, Soares A, Hantson J, Teixeira M, Sachs D, Valognes D, Scheer A, Schwarz MK, Wells TN, Proudfoot AE, Shaw J - Front Immunol (2012)

Inhibition of delayed-type hypersensitivity. Immunization was performed by s.c. administration of SRBC, followed by a challenge in the hindpaw 5 days later. The persulfated oligosaccharides (10 mg/kg) were administered 30 min prior and 8 h after the challenge. Dexamethasone was used as a positive control, and paw thickness was measured 21 h following the challenge. The statistical differences vs. the control group (mice challenged with SRBC and treated with vehicle for the compounds 0.02% BSA diluted in PBS) are shown whenever present and indicated by *P <0.05>; ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3472544&req=5

Figure 5: Inhibition of delayed-type hypersensitivity. Immunization was performed by s.c. administration of SRBC, followed by a challenge in the hindpaw 5 days later. The persulfated oligosaccharides (10 mg/kg) were administered 30 min prior and 8 h after the challenge. Dexamethasone was used as a positive control, and paw thickness was measured 21 h following the challenge. The statistical differences vs. the control group (mice challenged with SRBC and treated with vehicle for the compounds 0.02% BSA diluted in PBS) are shown whenever present and indicated by *P <0.05>; ***P < 0.001.
Mentions: Despite the fact that the peritoneal recruitment assay led to enhanced recruitment, we tested the anti-inflammatory potential of the sulfated GAG analogs in another model, delayed-type hypersensitivity. Initial experiments were performed in order to define the optimal dose and the regimen for the administration of MHxS. A dose-response experiment using 0.1, 1, and 10 mg/kg (dosing at −30 min and at +8 h post-challenge) was performed and statistically significant inhibitions were shown only for the highest dose (data not shown). In a subsequent experiment we tested whether we could alter the efficacy of MHxS in this model by varying the frequency of administrations while keeping the same dose of 10 mg/kg. We concluded that while the pre-administration of MHxS at −30 min was important for the observed effect, the administration of a pre-treatment dose 24 h before challenge on top of the dosings performed at −30 min and at +8 h did not further improve the inhibition in paw thickness-induced by MHxS. Finally, a head to head comparison of the efficacy of NisS, StachS, and MHxS was performed at the best conditions defined in earlier experiments, i.e., fixed dose of 10 mg/kg with compounds being administered at −30 min and +8 h post-challenge. These results are shown in Figure 5, where paw swelling was inhibited by treatment with NisS, StachS, and MHxS by an order of 20, 41, and 39% respectively in comparison to 47% for dexamethasone.

Bottom Line: In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation.However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment.In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.

View Article: PubMed Central - PubMed

Affiliation: Merck Serono Geneva Research Centre Geneva, Switzerland.

ABSTRACT
Heparin, a glycosaminoglycan (GAG), has both anti-inflammatory and anti-coagulant properties. The clinical use of heparin against inflammation, however, has been limited by concerns about increased bleeding. While the anti-coagulant activity of heparin is well understood, its anti-inflammatory properties are less so. Heparin is known to bind to certain cytokines, including chemokines, small proteins which mediate inflammation through their control of leukocyte migration and activation. Molecules which can interrupt the chemokine-GAG interaction without inhibiting coagulation could therefore, represent a new class of anti-inflammatory agents. In the present study, two approaches were undertaken, both focusing on the heparin-chemokine relationship. In the first, a structure based strategy was used: after an initial screening of potential small molecule binders using protein NMR on a target chemokine, binding molecules were optimized through structure-based design. In the second approach, commercially available short oligosaccharides were polysulfated. In vitro, these molecules prevented chemokine-GAG binding and chemokine receptor activation without disrupting coagulation. However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment. In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system.

No MeSH data available.


Related in: MedlinePlus