1.KRP-203, sphingosine 1-phosphate receptor type 1 agonist, ameliorates atherosclerosis in LDL-R-/- mice.
Potì F1, Gualtieri F, Sacchi S, Weißen-Plenz G, Varga G, Brodde M, Weber C, Simoni M, Nofer JR. Arterioscler Thromb Vasc Biol. 2013 Jul;33(7):1505-12. doi: 10.1161/ATVBAHA.113.301347. Epub 2013 May 2.
OBJECTIVE: Sphingosine 1-phosphate (S1P) partly accounts for antiatherogenic properties of high-density lipoproteins. We previously demonstrated that FTY720, a synthetic S1P analog targeting all S1P receptors but S1P receptor type 2, inhibits murine atherosclerosis. Here, we addressed the identity of S1P receptor mediating atheroprotective effects of S1P.
2.A novel sphingosine 1-phosphate receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), regulates chronic colitis in interleukin-10 gene-deficient mice.
Song J1, Matsuda C, Kai Y, Nishida T, Nakajima K, Mizushima T, Kinoshita M, Yasue T, Sawa Y, Ito T. J Pharmacol Exp Ther. 2008 Jan;324(1):276-83. Epub 2007 Sep 26.
Current treatments for patients with Crohn's disease (CD) are based on recent advances in elucidating the pathophysiology of the disease. A satisfactory therapeutic strategy has not been well established. A new sphingosine 1-phosphate (S1P) receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), has been developed for immunomodulation in autoimmune diseases and organ transplantation. We aimed to evaluate the efficacy and potency of KRP-203 on the treatment of chronic colitis in an interleukin (IL)-10 gene-deficient (IL-10(-/-)) mouse model. KRP-203 agonistic activity on S1P receptor was assessed in vitro. KRP-203 was administered for 1 or 4 weeks to IL-10(-/-) mice with clinical signs of colitis. The histological appearance of the colon and the numbers, phenotype, and cytokine production of lymphocytes were compared with a control group. KRP-203 treatment was effective in preventing body weight loss in the IL-10(-/-) colitis model.
3.A novel sphingosine-1-phosphate receptor agonist KRP-203 attenuates rat autoimmune myocarditis.
Ogawa R1, Takahashi M, Hirose S, Morimoto H, Ise H, Murakami T, Yasue T, Kuriyama K, Hongo M, Kobayashi E, Ikeda U. Biochem Biophys Res Commun. 2007 Sep 28;361(3):621-8. Epub 2007 Jul 23.
Sphingosine-1-phosphate (S1P) is an active sphingolipid metabolite that exerts important biological effects. Recently, we demonstrated that KRP-203 is a novel S1P receptor agonist that can alter lymphocyte homing and act as an immunomodulating agent. We investigated the efficacy of KRP-203 in the treatment of rat experimental autoimmune myocarditis. KRP-203 significantly attenuated the inflammation area, heart weight/body weight ratio, and left ventricular function. Immunohistochemical analysis and RT-PCR revealed that KRP-203 significantly decreased the infiltration of macrophages and CD4 T cells in the myocardium and the expression of inflammatory cytokines. Flow cytometric analysis revealed that treatment with KRP-203 effectively reduced the number of peripheral CD4 and CD8 T cells but not that of B cells and granulocytes. Further, late KRP-203 treatment was effective even against established EAM. These results demonstrate the therapeutic potential of KRP-203 for the treatment of human myocarditis and provide new insights into the pathogenesis of this disease.