Effect of Rebamipide
Effect of Rebamipide
Object. To clarify the mechanism(s) involved in the perivascular mobilization of granulocytes and macrophages by periarterial autologous blood (PAAB) in the vicinity of the femoral artery (FA) in rats, superoxide production as well as expression of intercellular adhesion molecule-1 (ICAM-1) were determined by conducting both in vitro and in vivo experiments.
Methods. In an in vitro study, a significant amount of superoxide inhibited by diphenyleneiodonium (20 µM and 100 µM) was identified at 3 hours after application of 10% whole blood to the aortic segments, and these results were correlated with in vitro ICAM-1 expression. High expression of ICAM-1 was subsequently demonstrated in these segments at 24 hours in in vitro and in vivo studies. In the in vivo study, an increased mobilization of granulocytes paralleled with a high expression of ICAM-1 in the vessels at 24 hours after administration of PAAB to the FA and then declined. Subsequently, macrophage infiltration progressively increased at all layers throughout a period of 7 to 12 days. Pretreatment with rebamipide (100 and 300 mg kg day , orally) significantly inhibited the expression of ICAM-1 with inhibition of mobilization of granulocyte/macrophage.
Conclusions. These findings suggest that application of PAAB to the rat FA causes superoxide-linked expression of ICAM-1 and mobilization of granulocyte and macrophages. Thus, the potential value in suppressing these variables stimulated by PAAB is indicated in therapeutic strategies for prevention and possible regression of vasospasm after subarachnoid hemorrhage.
Evidence reported in several studies indicates the importance of hemoglobin in the pathogenesis of vasospasm after SAH. A vasospasm model of rat FA in which whole blood was applied to the adventitial surface of the FA has been reported by Okada, et al., They demonstrated a chronic narrowing of the FA after the application of periadventitial blood, which was analogous in degree and in time course to that observed in cerebral vasospasm after SAH. This arteriopathy appears to be closely related with immunological and inflammatory responses based on several lines of evidence -- that is, the presence of inflammatory cells, increased levels of immunoglobulins and complements in the serum and vessel walls, and inhibition of the vasospasm by the antiinflammatory drugs and immunosuppressants. An expression of ICAM-1 was demonstrated at the intimal and medial layers of the basilar artery of SAH-induced rats and in the FA subjected to application of PAAB. Hemoglobin was demonstrated to generate the superoxide anion by autooxidation of hemoglobin to methemoglobin. With these results, a growing body of evidence has accumulated concerning the possible role of free radical reactions in the pathogenesis of prolonged cerebral vasospasm following SAH from ruptured intracranial aneurysms.
In our previous experiments we have documented the pharmacological actions of rebamipide, 2-(4-chlorobenzoylamino)-3-[2-(1H)-quinolinon-4-yl]propionic acid, in that it prevented ischemia/reperfusion-induced gastric mucosal damage through inhibition of mobilization of neutrophils via inhibition of production of reactive O2 species from activated neutrophils. Furthermore, it was shown to suppress the adherence of neutrophils to endothelial cells by inhibiting the expression of CD11b on neutrophils and interleukin-8 expression on the gastric epithelial cell. The evidence that adhesion-dependent inflammatory response is primarily mediated by expression of CD11b/CD18 on neutrophils and ICAM-1 on endothelial cells leads to the prediction that rebamipide may potentially inhibit the ICAM-1-coupled mobilization of granulocytes/macrophages.
To identify the superoxide anion-linked ICAM-1 expression, we measured superoxide anion production from an aortic segment on exposure to whole blood by lucigenin CL and expression of ICAM-1 by immunohistochemistry (in vitro). After application of autologous blood in the vicinity of rat FA (in vivo), we identified the SOD anion-linked ICAM-1 expression and mobilization of granulocyte/macrophage in the FA, and we further examined these variables after pretreatment with rebamipide.
Object. To clarify the mechanism(s) involved in the perivascular mobilization of granulocytes and macrophages by periarterial autologous blood (PAAB) in the vicinity of the femoral artery (FA) in rats, superoxide production as well as expression of intercellular adhesion molecule-1 (ICAM-1) were determined by conducting both in vitro and in vivo experiments.
Methods. In an in vitro study, a significant amount of superoxide inhibited by diphenyleneiodonium (20 µM and 100 µM) was identified at 3 hours after application of 10% whole blood to the aortic segments, and these results were correlated with in vitro ICAM-1 expression. High expression of ICAM-1 was subsequently demonstrated in these segments at 24 hours in in vitro and in vivo studies. In the in vivo study, an increased mobilization of granulocytes paralleled with a high expression of ICAM-1 in the vessels at 24 hours after administration of PAAB to the FA and then declined. Subsequently, macrophage infiltration progressively increased at all layers throughout a period of 7 to 12 days. Pretreatment with rebamipide (100 and 300 mg kg day , orally) significantly inhibited the expression of ICAM-1 with inhibition of mobilization of granulocyte/macrophage.
Conclusions. These findings suggest that application of PAAB to the rat FA causes superoxide-linked expression of ICAM-1 and mobilization of granulocyte and macrophages. Thus, the potential value in suppressing these variables stimulated by PAAB is indicated in therapeutic strategies for prevention and possible regression of vasospasm after subarachnoid hemorrhage.
Evidence reported in several studies indicates the importance of hemoglobin in the pathogenesis of vasospasm after SAH. A vasospasm model of rat FA in which whole blood was applied to the adventitial surface of the FA has been reported by Okada, et al., They demonstrated a chronic narrowing of the FA after the application of periadventitial blood, which was analogous in degree and in time course to that observed in cerebral vasospasm after SAH. This arteriopathy appears to be closely related with immunological and inflammatory responses based on several lines of evidence -- that is, the presence of inflammatory cells, increased levels of immunoglobulins and complements in the serum and vessel walls, and inhibition of the vasospasm by the antiinflammatory drugs and immunosuppressants. An expression of ICAM-1 was demonstrated at the intimal and medial layers of the basilar artery of SAH-induced rats and in the FA subjected to application of PAAB. Hemoglobin was demonstrated to generate the superoxide anion by autooxidation of hemoglobin to methemoglobin. With these results, a growing body of evidence has accumulated concerning the possible role of free radical reactions in the pathogenesis of prolonged cerebral vasospasm following SAH from ruptured intracranial aneurysms.
In our previous experiments we have documented the pharmacological actions of rebamipide, 2-(4-chlorobenzoylamino)-3-[2-(1H)-quinolinon-4-yl]propionic acid, in that it prevented ischemia/reperfusion-induced gastric mucosal damage through inhibition of mobilization of neutrophils via inhibition of production of reactive O2 species from activated neutrophils. Furthermore, it was shown to suppress the adherence of neutrophils to endothelial cells by inhibiting the expression of CD11b on neutrophils and interleukin-8 expression on the gastric epithelial cell. The evidence that adhesion-dependent inflammatory response is primarily mediated by expression of CD11b/CD18 on neutrophils and ICAM-1 on endothelial cells leads to the prediction that rebamipide may potentially inhibit the ICAM-1-coupled mobilization of granulocytes/macrophages.
To identify the superoxide anion-linked ICAM-1 expression, we measured superoxide anion production from an aortic segment on exposure to whole blood by lucigenin CL and expression of ICAM-1 by immunohistochemistry (in vitro). After application of autologous blood in the vicinity of rat FA (in vivo), we identified the SOD anion-linked ICAM-1 expression and mobilization of granulocyte/macrophage in the FA, and we further examined these variables after pretreatment with rebamipide.
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