Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1-phosphate receptors 1 and 5, in preclinical models of multiple sclerosis.

ONO-4641 is a next-generation sphingosine 1-phosphate (S1P) receptor agonist selective for S1P receptors 1 and 5. The objective of the study was to characterize the immunomodulatory effects of ONO-4641 using preclinical data. ONO-4641 was tested in both in-vitro pharmacological studies as well as in-vivo models of transient or relapsing-remitting experimental autoimmune encephalomyelitis (EAE). In vitro, ONO-4641 showed highly potent agonistic activities versus S1P receptors 1 and 5 [half maximal effective concentration (EC(50) ) values of 0·0273 and 0·334 nM, respectively], and had profound S1P receptor 1 down-regulating effects on the cell membrane. ONO-4641 decreased peripheral blood lymphocyte counts in rats by inhibiting lymphocyte egress from secondary lymphoid tissues. In a rat experimental autoimmune encephalomyelitis (EAE) model, ONO-4641 suppressed the onset of disease and inhibited lymphocyte infiltration into the spinal cord in a dose-dependent manner at doses of 0·03 and 0·1 mg/kg. Furthermore, ONO-4641 prevented relapse of disease in a non-obese diabetic mouse model of relapsing-remitting EAE. These observations suggest that ONO-4641 may provide therapeutic benefits in the treatment of multiple sclerosis.

Serum-deprivation induces cell death of rat cultured microglia accompanied with expression of Bax protein.

Expression of Bcl-2 related proteins in rat microglial primary culture was examined. At relative low cell densities, serum deprivation caused cell death and nuclei condensation of cultured microglia. Expression of a pro-apoptotic protein, Bax, but not Bcl-2, was increased by the serum deprivation. SB203580, a specific inhibitor of p38MAPK, prevented both the serum deprivation-induced Bax expression and microglial death. Immunochemical staining showed that microglia expressing a high level of Bax were subjected to apoptosis-like cell death. These observations suggest that Bax expression underlies the apoptosis of cultured microglia after serum deprivation.

[Twenty-year follow-up of visual field defects in primary glaucoma eyes].

PURPOSE: The time course of visual field defects in patients with primary glaucoma was investigated for 20 or more years. METHODS: The subjects were 51 eyes of 29 patients (open angle glaucoma, 40 eyes of 21 patients angle closure glaucoma, 11 eyes of 8 patients). The mean intraocular pressure of these subjects was within 21 mmHg during the follow-up periods. All the eyes were monitored with Goldmann's perimetry, and the visual field was graded using Kozaki's classification. RESULTS: At the 20-year follow-up, 68% of the open angle cases and 45% of the angle closure cases had significant progression of visual field defects. There was no significant difference in average intraocular pressure during the follow-up period between the progression group and the stable group. CONCLUSION: These results suggested that, in a follow-up of twenty years, visual field defects both in primary open angle glaucoma and chronic angle closure glaucoma can progress frequently, even if the intraocular pressure of these patients was well controlled.