his study was conducted to investigate putative antagonism of integrin receptors alpha(M)beta(2) and alpha(L)beta(2) by a novel coumarin derivative (BOL-303225-A), its efficacy in-vivo after retinal ischaemia-reperfusion injury, and its bioavailability in rat plasma. A cellular adhesion assay in Jurkat and U937 cells, and a flow cytometry assay with an antibody against the beta(2) subunit were conducted. BOL-303225-A bioavailability in rat plasma and the retinal levels of myeloperoxidase (MPO) after ischaemia-reperfusion injury were evaluated after oral administration (10 mg kg(-1)). In-vitro cell viability assays revealed no cytotoxicity for BOL-303225-A over a wide dose range, and IC50 values of 32.3 +/- 1.5 muM and 84.95 +/- 2.3 muM were found for Jurkat and U937 cells, respectively. The drug showed specific binding to the alpha(M)beta(2) and alpha(L)beta(2) integrin receptors expressed by U937 and Jurkat cells, respectively, producing a fluorescence shift towards lower values in a concentration-dependent manner. The pharmacokinetic profile of BOL-303225-A exhibited rapid absorption following oral administration in the rat. A significant reduction of retinal MPO levels was observed in drug-treated rats. This study demonstrated that BOL-303225-A acts as an antagonist of the integrin alpha(L)beta(2) and alpha(M)beta(2) receptors, suggesting that this drug could be used for ocular diseases such as diabetic retinopathy.

New coumarin-based anti-inflammatory drug: putative antagonist of the integrins alpha(L)beta(2) and alpha(M)beta(2).

BUCOLO, CLAUDIO;BAIULA, MONICA;SPARTÀ, ANTONINO MARIA;SPAMPINATO, SANTI MARIO
2008

Abstract

his study was conducted to investigate putative antagonism of integrin receptors alpha(M)beta(2) and alpha(L)beta(2) by a novel coumarin derivative (BOL-303225-A), its efficacy in-vivo after retinal ischaemia-reperfusion injury, and its bioavailability in rat plasma. A cellular adhesion assay in Jurkat and U937 cells, and a flow cytometry assay with an antibody against the beta(2) subunit were conducted. BOL-303225-A bioavailability in rat plasma and the retinal levels of myeloperoxidase (MPO) after ischaemia-reperfusion injury were evaluated after oral administration (10 mg kg(-1)). In-vitro cell viability assays revealed no cytotoxicity for BOL-303225-A over a wide dose range, and IC50 values of 32.3 +/- 1.5 muM and 84.95 +/- 2.3 muM were found for Jurkat and U937 cells, respectively. The drug showed specific binding to the alpha(M)beta(2) and alpha(L)beta(2) integrin receptors expressed by U937 and Jurkat cells, respectively, producing a fluorescence shift towards lower values in a concentration-dependent manner. The pharmacokinetic profile of BOL-303225-A exhibited rapid absorption following oral administration in the rat. A significant reduction of retinal MPO levels was observed in drug-treated rats. This study demonstrated that BOL-303225-A acts as an antagonist of the integrin alpha(L)beta(2) and alpha(M)beta(2) receptors, suggesting that this drug could be used for ocular diseases such as diabetic retinopathy.
Bucolo C.; Maltese A.; Maugeri F.; Ward K.W.; Baiula M.; Spartà A.; Spampinato S.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/63569
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