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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

Inhibition of α2β1 integrin has anti-inflammatory effect in adjuvant-induced arthritis model. The male Lewis inbred rats were injected with 0.5 mg of killed Mycobacterium butyrium. Vehicle (n = 10), Diclofenac-Na (2 mg/kg, n = 10) and BTT-3016 (5 mg/kg, n = 10) were administrated i.p. once a day from day 1 to 27 after the challenge. The severity of the disease was determined by (A) scoring and by (B) measuring the volume of left hind paw at time points indicated. (A, B) The data are represented as mean ± SEM. **P < 0.01; ***P < 0.001 (ANOVA followed by Newman-Keuls multiple comparison test).
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fig05: Inhibition of α2β1 integrin has anti-inflammatory effect in adjuvant-induced arthritis model. The male Lewis inbred rats were injected with 0.5 mg of killed Mycobacterium butyrium. Vehicle (n = 10), Diclofenac-Na (2 mg/kg, n = 10) and BTT-3016 (5 mg/kg, n = 10) were administrated i.p. once a day from day 1 to 27 after the challenge. The severity of the disease was determined by (A) scoring and by (B) measuring the volume of left hind paw at time points indicated. (A, B) The data are represented as mean ± SEM. **P < 0.01; ***P < 0.001 (ANOVA followed by Newman-Keuls multiple comparison test).

Mentions: To test, whether α2β1 integrin inhibitors can inhibit the signs of chronic inflammation we tested the potency of intraperitoneally administered BTT-3016 (5 mg/kg, once a day) in a rat model of adjuvant-induced arthritis. Orally administered diclofenac (2 mg/kg, twice a day) was used as a positive control. BTT-3016 treatment reduced substantially and statistically significantly the score reflecting the clinical severity of the arthritis (Fig.5A). The effect was comparable with that caused by the reference compound diclofenac (Fig.5A). BTT-3016 also significantly decreased the volume of angle edema, but the effect was smaller than that of diclofenac (Fig.5B). Thus, in principle small molecule inhibitors of α2β1 integrin are effective anti-inflammatory compounds in chronic inflammation.


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)

Inhibition of α2β1 integrin has anti-inflammatory effect in adjuvant-induced arthritis model. The male Lewis inbred rats were injected with 0.5 mg of killed Mycobacterium butyrium. Vehicle (n = 10), Diclofenac-Na (2 mg/kg, n = 10) and BTT-3016 (5 mg/kg, n = 10) were administrated i.p. once a day from day 1 to 27 after the challenge. The severity of the disease was determined by (A) scoring and by (B) measuring the volume of left hind paw at time points indicated. (A, B) The data are represented as mean ± SEM. **P < 0.01; ***P < 0.001 (ANOVA followed by Newman-Keuls multiple comparison test).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig05: Inhibition of α2β1 integrin has anti-inflammatory effect in adjuvant-induced arthritis model. The male Lewis inbred rats were injected with 0.5 mg of killed Mycobacterium butyrium. Vehicle (n = 10), Diclofenac-Na (2 mg/kg, n = 10) and BTT-3016 (5 mg/kg, n = 10) were administrated i.p. once a day from day 1 to 27 after the challenge. The severity of the disease was determined by (A) scoring and by (B) measuring the volume of left hind paw at time points indicated. (A, B) The data are represented as mean ± SEM. **P < 0.01; ***P < 0.001 (ANOVA followed by Newman-Keuls multiple comparison test).
Mentions: To test, whether α2β1 integrin inhibitors can inhibit the signs of chronic inflammation we tested the potency of intraperitoneally administered BTT-3016 (5 mg/kg, once a day) in a rat model of adjuvant-induced arthritis. Orally administered diclofenac (2 mg/kg, twice a day) was used as a positive control. BTT-3016 treatment reduced substantially and statistically significantly the score reflecting the clinical severity of the arthritis (Fig.5A). The effect was comparable with that caused by the reference compound diclofenac (Fig.5A). BTT-3016 also significantly decreased the volume of angle edema, but the effect was smaller than that of diclofenac (Fig.5B). Thus, in principle small molecule inhibitors of α2β1 integrin are effective anti-inflammatory compounds in chronic inflammation.

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