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Sulfonamide inhibitors of α2β1 integrin reveal the essential role of collagen receptors in in vivo models of inflammation.

Nissinen L, Ojala M, Langen B, Dost R, Pihlavisto M, Käpylä J, Marjamäki A, Heino J - Pharmacol Res Perspect (2015)

Bottom Line: Since α2β1 integrin is abundantly expressed on various inflammation-associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti-inflammatory properties.Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid-induced ear edema, PAF stimulated air pouch, ovalbumin-induced skin hypersensitivity, adjuvant arthritis, and collagen-induced arthritis.Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Turku 20014, Turku, Finland ; Biotie Therapies Corp Turku, Finland.

ABSTRACT
Small molecule inhibitors of α2β1 integrin, a major cellular collagen receptor, have been reported to inhibit platelet function, kidney injury, and angiogenesis. Since α2β1 integrin is abundantly expressed on various inflammation-associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti-inflammatory properties. Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid-induced ear edema, PAF stimulated air pouch, ovalbumin-induced skin hypersensitivity, adjuvant arthritis, and collagen-induced arthritis. Thus, these sulfonamides are potential drugs for acute and allergic inflammation, hypersensitivity, and arthritis. One sulfonamide with potent anti-inflammatory activity has previously been reported to be selective for activated integrins, but not to inhibit platelet function. Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.

No MeSH data available.


Related in: MedlinePlus

Both BTT-3033 and BTT-3034 demonstrate moderate anti-inflammatory effect in an acute inflammation model of mouse. The inflammatory response was induced with arachidonic acid (20 μL of 164 mmol/L solution in acetone) on left ears. The indicated concentrations of BTT-3033 and BTT-3034, dexamethasone (Dexam, 0.1 mg/kg, n = 6), and vehicle were administrated p.o. once daily 48 h, 24 h, and 3 h before arachidonic acid challenge. The number of mice in each group was 6. Ear thickness was measured 60 min after arachidonic acid challenge. The data are presented as mean ± SEM. **P < 0.01; ***P < 0.001 (One-way ANOVA followed by Bonferroni’s post hoc comparisons tests).
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fig02: Both BTT-3033 and BTT-3034 demonstrate moderate anti-inflammatory effect in an acute inflammation model of mouse. The inflammatory response was induced with arachidonic acid (20 μL of 164 mmol/L solution in acetone) on left ears. The indicated concentrations of BTT-3033 and BTT-3034, dexamethasone (Dexam, 0.1 mg/kg, n = 6), and vehicle were administrated p.o. once daily 48 h, 24 h, and 3 h before arachidonic acid challenge. The number of mice in each group was 6. Ear thickness was measured 60 min after arachidonic acid challenge. The data are presented as mean ± SEM. **P < 0.01; ***P < 0.001 (One-way ANOVA followed by Bonferroni’s post hoc comparisons tests).

Mentions: In the further experiments, the anti-inflammatory effects of BTT-3033 and BTT-3034 were tested using arachidonic acid-induced ear edema (Fig.2), a mouse model of acute inflammation (Young et al., 1984; Chang et al., 1986; Van der Mey et al., 2003). Sulfonamides were administrated orally 48 h, 24 h, and 3 h before ear swelling was induced by application of arachidonic acid. When ear swelling was measured 60 min later both BTT-3033 (10 mg/kg, P < 0.01) and BTT-3034 (2.5 mg/kg, P < 0.001; 10 mg/kg, P < 0.001) were clearly effective. However, they did not reach the potency of a reference compound (dexamethasone, 0.1 mg/kg). Thus, again inhibition of α2β1 integrin function was shown to have moderate anti-inflammatory effects and BTT-3034 was more effective than BTT-3033.


Sulfonamide inhibitors of α2β1 integrin reveal the essential role of collagen receptors in in vivo models of inflammation.

Nissinen L, Ojala M, Langen B, Dost R, Pihlavisto M, Käpylä J, Marjamäki A, Heino J - Pharmacol Res Perspect (2015)

Both BTT-3033 and BTT-3034 demonstrate moderate anti-inflammatory effect in an acute inflammation model of mouse. The inflammatory response was induced with arachidonic acid (20 μL of 164 mmol/L solution in acetone) on left ears. The indicated concentrations of BTT-3033 and BTT-3034, dexamethasone (Dexam, 0.1 mg/kg, n = 6), and vehicle were administrated p.o. once daily 48 h, 24 h, and 3 h before arachidonic acid challenge. The number of mice in each group was 6. Ear thickness was measured 60 min after arachidonic acid challenge. The data are presented as mean ± SEM. **P < 0.01; ***P < 0.001 (One-way ANOVA followed by Bonferroni’s post hoc comparisons tests).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492762&req=5

fig02: Both BTT-3033 and BTT-3034 demonstrate moderate anti-inflammatory effect in an acute inflammation model of mouse. The inflammatory response was induced with arachidonic acid (20 μL of 164 mmol/L solution in acetone) on left ears. The indicated concentrations of BTT-3033 and BTT-3034, dexamethasone (Dexam, 0.1 mg/kg, n = 6), and vehicle were administrated p.o. once daily 48 h, 24 h, and 3 h before arachidonic acid challenge. The number of mice in each group was 6. Ear thickness was measured 60 min after arachidonic acid challenge. The data are presented as mean ± SEM. **P < 0.01; ***P < 0.001 (One-way ANOVA followed by Bonferroni’s post hoc comparisons tests).
Mentions: In the further experiments, the anti-inflammatory effects of BTT-3033 and BTT-3034 were tested using arachidonic acid-induced ear edema (Fig.2), a mouse model of acute inflammation (Young et al., 1984; Chang et al., 1986; Van der Mey et al., 2003). Sulfonamides were administrated orally 48 h, 24 h, and 3 h before ear swelling was induced by application of arachidonic acid. When ear swelling was measured 60 min later both BTT-3033 (10 mg/kg, P < 0.01) and BTT-3034 (2.5 mg/kg, P < 0.001; 10 mg/kg, P < 0.001) were clearly effective. However, they did not reach the potency of a reference compound (dexamethasone, 0.1 mg/kg). Thus, again inhibition of α2β1 integrin function was shown to have moderate anti-inflammatory effects and BTT-3034 was more effective than BTT-3033.

Bottom Line: Since α2β1 integrin is abundantly expressed on various inflammation-associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti-inflammatory properties.Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid-induced ear edema, PAF stimulated air pouch, ovalbumin-induced skin hypersensitivity, adjuvant arthritis, and collagen-induced arthritis.Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Turku 20014, Turku, Finland ; Biotie Therapies Corp Turku, Finland.

ABSTRACT
Small molecule inhibitors of α2β1 integrin, a major cellular collagen receptor, have been reported to inhibit platelet function, kidney injury, and angiogenesis. Since α2β1 integrin is abundantly expressed on various inflammation-associated cells, we tested whether recently developed α2β1 blocking sulfonamides have anti-inflammatory properties. Integrin α2β1 inhibitors were shown to reduce the signs of inflammation in arachidonic acid-induced ear edema, PAF stimulated air pouch, ovalbumin-induced skin hypersensitivity, adjuvant arthritis, and collagen-induced arthritis. Thus, these sulfonamides are potential drugs for acute and allergic inflammation, hypersensitivity, and arthritis. One sulfonamide with potent anti-inflammatory activity has previously been reported to be selective for activated integrins, but not to inhibit platelet function. Thus, the experiments also revealed fundamental differences in the action of nonactivated and activated α2β1 integrins in inflammation when compared to thrombosis.

No MeSH data available.


Related in: MedlinePlus