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Activity of the lipoxygenase inhibitor 1-phenyl-3-pyrazolidinone (phenidone) and derivatives on the inhibition of adhesion molecule expression on human umbilical vascular endothelial cells.

Schroeder TH, Krueger WA, Dieterich HJ, Nohé B - Biologics (2008)

Bottom Line: TNF-alpha stimulated human umbilical venous endothelial cells (HUVECs) were incubated with phenidone, 4-methyl-phenidone, 4-4-dimethyl-phenidone, 5-methyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone.The inhibition of endothelial cell expression on HUVECs was measured by flow cytometry.Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic inflammation during shock, trauma, and sepsis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anaesthesiology and Critical Care Medicine, Tuebingen University Hospital, Tuebingen, Germany.

ABSTRACT
Leukocyte adhesion contributes to perfusion abnormalities and tissue damage during trauma, shock or overwhelming inflammation. This study was performed to determine whether the lipoxygenase inhibitor phenidone and derivatives decrease the expression of adhesion molecules on tumor necrosis factor-alpha (TNF-alpha) stimulated endothelial cells and attenuate leukocyte-endothelial interactions under flow in vitro. TNF-alpha stimulated human umbilical venous endothelial cells (HUVECs) were incubated with phenidone, 4-methyl-phenidone, 4-4-dimethyl-phenidone, 5-methyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone. We tested the inhibition of adhesion molecule expression at different inhibitor concentrations before, during, and after the stimulation of HUVECs. The inhibition of endothelial cell expression on HUVECs was measured by flow cytometry. Rolling and firm adhesion of leukocytes to pretreated endothelium was examined in a parallel plate flow chamber. Phenidone inhibited the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial-leukocyte adhesion molecule-1 on HUVECs when added prior to HUVEC stimulation. The inhibitory effect of phenidone was still observed when added simultaneously, but not when added after HUVEC stimulation. 4-4-dimethyl-phenidone and 5-phenyl-phenidone inhibited the expression of adhesion molecules more effectively than phenidone. The attenuation of leukocyte rolling under flow conditions was also significantly more effective with 4-4-dimethyl-phenidone than with phenidone. Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic inflammation during shock, trauma, and sepsis.

No MeSH data available.


Related in: MedlinePlus

Inhibition of ICAM-1, VCAM-1, and E-selectin by phenidone and derivatives.IC50: The inhibitor concentration yielding 50% inhibition of adhesion molecule expression. *=significant reduction of ICAM-1, and E-selectin expression after preincubation with the denoted derivative, compared to phenidone (p < 0.01).
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f4-btt-2-151: Inhibition of ICAM-1, VCAM-1, and E-selectin by phenidone and derivatives.IC50: The inhibitor concentration yielding 50% inhibition of adhesion molecule expression. *=significant reduction of ICAM-1, and E-selectin expression after preincubation with the denoted derivative, compared to phenidone (p < 0.01).

Mentions: The ability of the phenidone derivatives 4-methyl-phenidone, 5-methyl-phenidone, 4-4-dimethyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone to inhibit the adhesion molecule expression on HUVECs was tested when they were administered before the activation of HUVECs (pre-incubation). HUVECs were incubated with increasing concentrations of the derivatives between 125 and 2000 μM. All experiments were repeated at least three times. To quantify the ability of the derivatives to inhibit adhesion molecule expression, we calculated the inhibitor concentration that lead to a 50% inhibition of adhesion molecule expression (IC50), assuming a logarithmic dose-response relationship. The results are shown in Figure 4. The expression of ICAM-1 was significantly reduced after pre-incubation of HUVECs with 4-4-dimethyl-phenidone and 5-phenyl-phenidone (IC50 382 ± 67 μM and 202 ± 102 μM, respectively) (p < 0.01) compared with the inhibition of adhesion molecule expression by phenidone (IC50 1128 ± 371 μM). Similarly, the expression of E-selectin was significantly reduced with these two compounds (IC50 216 ± 138 μM and 169 ± 41 μM) compared to phenidone (IC50 861 ± 338 μM). In contrast, 4-methyl-phenidone and 5-methyl-phenidone did not reduce adhesion molecule expression more effectively than phenidone (4-methyl-phenidone: IC50 of 1542 ± 1062 μM for ICAM-1 and 619 ± 183 μM for E.-selectin; 5-methyl-phenidone: IC50 1615 ± 819 for ICAM-1 and 1461 ± 774 μM for E-selectin). No inhibition of the adhesion molecule expression was observed with 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone (not shown). Also, compared with phenidone, the expression of VCAM-1 was not significantly reduced after pre-incubation with any of the tested derivatives.


Activity of the lipoxygenase inhibitor 1-phenyl-3-pyrazolidinone (phenidone) and derivatives on the inhibition of adhesion molecule expression on human umbilical vascular endothelial cells.

Schroeder TH, Krueger WA, Dieterich HJ, Nohé B - Biologics (2008)

Inhibition of ICAM-1, VCAM-1, and E-selectin by phenidone and derivatives.IC50: The inhibitor concentration yielding 50% inhibition of adhesion molecule expression. *=significant reduction of ICAM-1, and E-selectin expression after preincubation with the denoted derivative, compared to phenidone (p < 0.01).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2727783&req=5

f4-btt-2-151: Inhibition of ICAM-1, VCAM-1, and E-selectin by phenidone and derivatives.IC50: The inhibitor concentration yielding 50% inhibition of adhesion molecule expression. *=significant reduction of ICAM-1, and E-selectin expression after preincubation with the denoted derivative, compared to phenidone (p < 0.01).
Mentions: The ability of the phenidone derivatives 4-methyl-phenidone, 5-methyl-phenidone, 4-4-dimethyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone to inhibit the adhesion molecule expression on HUVECs was tested when they were administered before the activation of HUVECs (pre-incubation). HUVECs were incubated with increasing concentrations of the derivatives between 125 and 2000 μM. All experiments were repeated at least three times. To quantify the ability of the derivatives to inhibit adhesion molecule expression, we calculated the inhibitor concentration that lead to a 50% inhibition of adhesion molecule expression (IC50), assuming a logarithmic dose-response relationship. The results are shown in Figure 4. The expression of ICAM-1 was significantly reduced after pre-incubation of HUVECs with 4-4-dimethyl-phenidone and 5-phenyl-phenidone (IC50 382 ± 67 μM and 202 ± 102 μM, respectively) (p < 0.01) compared with the inhibition of adhesion molecule expression by phenidone (IC50 1128 ± 371 μM). Similarly, the expression of E-selectin was significantly reduced with these two compounds (IC50 216 ± 138 μM and 169 ± 41 μM) compared to phenidone (IC50 861 ± 338 μM). In contrast, 4-methyl-phenidone and 5-methyl-phenidone did not reduce adhesion molecule expression more effectively than phenidone (4-methyl-phenidone: IC50 of 1542 ± 1062 μM for ICAM-1 and 619 ± 183 μM for E.-selectin; 5-methyl-phenidone: IC50 1615 ± 819 for ICAM-1 and 1461 ± 774 μM for E-selectin). No inhibition of the adhesion molecule expression was observed with 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone (not shown). Also, compared with phenidone, the expression of VCAM-1 was not significantly reduced after pre-incubation with any of the tested derivatives.

Bottom Line: TNF-alpha stimulated human umbilical venous endothelial cells (HUVECs) were incubated with phenidone, 4-methyl-phenidone, 4-4-dimethyl-phenidone, 5-methyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone.The inhibition of endothelial cell expression on HUVECs was measured by flow cytometry.Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic inflammation during shock, trauma, and sepsis.

View Article: PubMed Central - PubMed

Affiliation: Department of Anaesthesiology and Critical Care Medicine, Tuebingen University Hospital, Tuebingen, Germany.

ABSTRACT
Leukocyte adhesion contributes to perfusion abnormalities and tissue damage during trauma, shock or overwhelming inflammation. This study was performed to determine whether the lipoxygenase inhibitor phenidone and derivatives decrease the expression of adhesion molecules on tumor necrosis factor-alpha (TNF-alpha) stimulated endothelial cells and attenuate leukocyte-endothelial interactions under flow in vitro. TNF-alpha stimulated human umbilical venous endothelial cells (HUVECs) were incubated with phenidone, 4-methyl-phenidone, 4-4-dimethyl-phenidone, 5-methyl-phenidone, 5-phenyl-phenidone, and 5-methyl-1,(2,5-di-chloro-phenyl)-3-pyrazolidone. We tested the inhibition of adhesion molecule expression at different inhibitor concentrations before, during, and after the stimulation of HUVECs. The inhibition of endothelial cell expression on HUVECs was measured by flow cytometry. Rolling and firm adhesion of leukocytes to pretreated endothelium was examined in a parallel plate flow chamber. Phenidone inhibited the expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial-leukocyte adhesion molecule-1 on HUVECs when added prior to HUVEC stimulation. The inhibitory effect of phenidone was still observed when added simultaneously, but not when added after HUVEC stimulation. 4-4-dimethyl-phenidone and 5-phenyl-phenidone inhibited the expression of adhesion molecules more effectively than phenidone. The attenuation of leukocyte rolling under flow conditions was also significantly more effective with 4-4-dimethyl-phenidone than with phenidone. Lipoxygenase inhibitors might be of therapeutically interest for the treatment of overwhelming systemic inflammation during shock, trauma, and sepsis.

No MeSH data available.


Related in: MedlinePlus