Comparative Study of Glucocorticoids, Cyclosporine A, and JTE-607 [(-)-Ethyl-N-{3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl}-l-phenylalaninate Dihydrochloride] in a Mouse Septic Shock Model

Actions of glucocorticoids, cyclosporine A, and JTE-607 [(-)-ethyl- N -{3,5-dichloro-2-hydroxy-4-[2-(4-methylpiperazin-1-yl)ethoxy]benzoyl}-l-phenylalaninate dihydrochloride], a proinflammatory cytokine inhibitor that does not inhibit interleukin (IL)-2 or interferon-γ, were compared in a mouse septic shock model induced by cecal ligation and puncture (CLP). CLP caused elevation of macrophage inflammatory protein (MIP)-2 in lung, and MIP-2 and IL-6 in plasma and peritoneal fluid, reaching a peak 4 to 8 h after CLP. Myeloperoxidase (MPO) activity in lung increased and reached a peak 8 to 12 h after CLP. Acute treatment (subcutaneous injections 1 h before and 2 h after CLP) of mice with JTE-607 and methylprednisolone showed significant inhibition of elevated cytokine levels and MPO activity, plus increased survival rate. Similar treatment with cyclosporine A and prednisolone was ineffective. Chronic treatment (subcutaneous injection for seven consecutive days before CLP) of mice with JTE-607 also showed an inhibitory effect on cytokine production, MPO activity and mortality. In contrast, chronic treatment with cyclosporine A and prednisolone did not inhibit cytokine production or MPO activity, but rather exacerbated mortality. These results indicate that JTE-607 has protective effect on mouse mortality induced by CLP, correlating with inhibition of proinflammatory cytokines, whereas the immunosuppressants cyclosporine A and prednisolone do not. This suggests that JTE-607, a multiple cytokine inhibitor that does not cause adverse immunosuppression, is useful for treatment of septic shock.