No abstract

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of five G protein-coupled receptors (S1P1–S1P5). S1P1 is a major regulator of lymphocyte trafficking, and fingolimod, whose active metabolite fingolimod phosphate acts as a nonselective S1P receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating the lymphocyte trafficking by inducing down regulation of lymphocyte S1P1. Here, we detail the pharmacological profile of 5-{5-[3-(trifluoromethyl)-4-{[(2S)-1,1,1-trifluoropropan-2-yl]oxy}phenyl]-1,2,4-oxadiazol-3-yl}-1H-benzimidazole (ASP4058), a novel next-generation S1P receptor agonist selective for S1P1 and S1P5. ASP4058 preferentially activates S1P1 and S1P5 compared with S1P2, 3, 4 in GTPγS binding assays in vitro. Oral administration of ASP4058 reduced the number of peripheral lymphocytes and inhibited the development of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Further, ASP4058 prevented relapse of disease in a mouse model of relapsing-remitting EAE. Although these immunomodulatory effects were comparable to those of fingolimod, ASP4058 showed a wider safety margin than fingolimod for bradycardia and bronchoconstriction in rodents. These observations suggest that ASP4058 represents a new therapeutic option for treating multiple sclerosis that is safer than nonselective S1P receptor agonists such as fingolimod.

We previously identified a novel endogenous substance, serofendic acid, from a lipophilic extract of fetal calf serum. Serofendic acid protects cultured cortical neurons against the cytotoxicity of glutamate and nitric oxide. Here, we reported the protective effect of serofendic acid on reactive oxygen speciesinduced oxidative stress using primary rat striatal cultures. In addition, we compared the neuroprotective effect and the radical-scavenging activity of serofendic acid with those of dimethyl sulfoxide (DMSO), because serofendic acid possesses a DMSO structure. Paraquat caused neuronal death, which was inhibited by a cell-permeable superoxide dismutase (SOD) mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (Mn-TBAP); a cell-permeable SOD/catalase mimetic, EUK-134 [manganese 3-methoxy N,NЈ-bis(salicylidene)ethylenediamine chloride]; and a ferrous ion chelator, 2,2Ј-dipyridyl, in rat striatal cultures. Serofendic acid (10 -100 M) suppressed the neurotoxicity of paraquat, whereas DMSO (10 -100 M) did not. By contrast, higher concentrations (30 -300 mM) of DMSO ameliorated the paraquat-induced cell death. Furthermore, H 2 O 2 induced neurotoxicity, which was prevented by EUK-134 and 2,2Ј-dipyridyl. Serofendic acid (10 -100 M) also protected striatal neurons against the H 2 O 2 -induced toxicity. Higher concentrations (30 -300 mM) of DMSO ameliorated H 2 O 2 -induced neuronal death, whereas lower concentrations (10 -100 M) did not. Electron spin resonance spectrometry with a spin-trapping technique revealed that serofendic acid and DMSO had approximately the same ability to inhibit the formation of the hydroxyl radical (⅐OH). These results suggest that the ⅐OH-scavenging activity of serofendic acid is attributable to its DMSO structure and that the remaining components such as the atisane structure play an important role in eliciting neuroprotection at a concentration range of 10 to 100 M.

No abstract

These results support the potential of ASP2409 as an improved CTLA4-Ig for maintenance immunosuppression in organ transplantation.