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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

α2β1 integrin inhibitor BTT-3034 presents anti-inflammatory effect in collagen-induced arthritis model. Male DBA/1JNCrlj mice were challenged with bovine type II collagen and Freud′s adjuvant. Vehicle (n = 11), BTT-3033 (10 mg/kg, n = 10) and BTT-3034 (10 mg/kg, n = 10) were administrated orally twice a day and dexamethasone (Dexam, 0.1 mg/kg, n = 10) once a day from day 1 to 26 after the challenge. The severity of arthritis was evaluated with (A) paw thickness score, (B) paw redness score, and (C) paw edema score at time points indicated. (A–C) The data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 (Two-Way ANOVA with the post hoc Tukey’s test).
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fig06: α2β1 integrin inhibitor BTT-3034 presents anti-inflammatory effect in collagen-induced arthritis model. Male DBA/1JNCrlj mice were challenged with bovine type II collagen and Freud′s adjuvant. Vehicle (n = 11), BTT-3033 (10 mg/kg, n = 10) and BTT-3034 (10 mg/kg, n = 10) were administrated orally twice a day and dexamethasone (Dexam, 0.1 mg/kg, n = 10) once a day from day 1 to 26 after the challenge. The severity of arthritis was evaluated with (A) paw thickness score, (B) paw redness score, and (C) paw edema score at time points indicated. (A–C) The data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 (Two-Way ANOVA with the post hoc Tukey’s test).

Mentions: In another series of experiments arthritis in DBA/1J mice was induced by two immunizations with bovine collagen type II in the interval of 3 weeks. This disease model is influenced by the activity of α2β1-positive Th17 cell. Furthermore, the antibodies against α2β1 have been reported to decrease the severity of arthritis (El Azreq et al. 2013). Dexamethasone significantly reduced paw edema, thickness, and redness. BTT-3033 (10 mg/kg) had no statistically significant effects. BTT-3034 (10 mg/kg) significantly suppressed paw thickness (Fig.6A) but not paw redness (Fig.6B) or paw edema (Fig.6C). The results with BTT-3034 confirm the data from BTT-3016 experiments. Weaker potency of BTT-3034 is most probably due to its relative short half-life in plasma.


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)

α2β1 integrin inhibitor BTT-3034 presents anti-inflammatory effect in collagen-induced arthritis model. Male DBA/1JNCrlj mice were challenged with bovine type II collagen and Freud′s adjuvant. Vehicle (n = 11), BTT-3033 (10 mg/kg, n = 10) and BTT-3034 (10 mg/kg, n = 10) were administrated orally twice a day and dexamethasone (Dexam, 0.1 mg/kg, n = 10) once a day from day 1 to 26 after the challenge. The severity of arthritis was evaluated with (A) paw thickness score, (B) paw redness score, and (C) paw edema score at time points indicated. (A–C) The data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 (Two-Way ANOVA with the post hoc Tukey’s test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig06: α2β1 integrin inhibitor BTT-3034 presents anti-inflammatory effect in collagen-induced arthritis model. Male DBA/1JNCrlj mice were challenged with bovine type II collagen and Freud′s adjuvant. Vehicle (n = 11), BTT-3033 (10 mg/kg, n = 10) and BTT-3034 (10 mg/kg, n = 10) were administrated orally twice a day and dexamethasone (Dexam, 0.1 mg/kg, n = 10) once a day from day 1 to 26 after the challenge. The severity of arthritis was evaluated with (A) paw thickness score, (B) paw redness score, and (C) paw edema score at time points indicated. (A–C) The data are shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 (Two-Way ANOVA with the post hoc Tukey’s test).
Mentions: In another series of experiments arthritis in DBA/1J mice was induced by two immunizations with bovine collagen type II in the interval of 3 weeks. This disease model is influenced by the activity of α2β1-positive Th17 cell. Furthermore, the antibodies against α2β1 have been reported to decrease the severity of arthritis (El Azreq et al. 2013). Dexamethasone significantly reduced paw edema, thickness, and redness. BTT-3033 (10 mg/kg) had no statistically significant effects. BTT-3034 (10 mg/kg) significantly suppressed paw thickness (Fig.6A) but not paw redness (Fig.6B) or paw edema (Fig.6C). The results with BTT-3034 confirm the data from BTT-3016 experiments. Weaker potency of BTT-3034 is most probably due to its relative short half-life in plasma.

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