Journal: Nature Communications
Article Title: Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist
doi: 10.1038/s41467-024-49893-8
Figure Lengend Snippet: a Prophylactical efficacy of KSI-6666 (15 mg/kg/day) in rat EAE model. Rats were immunized by the intradermal injection of the syngeneic CNS antigen emulsified in complete Freund’s adjuvant. On the next day of the immunization, oral administration of compounds twice daily was started and lasted for 12 days. The clinical score and area under curve (AUC) of the score over time were evaluated in each group. Statistical analyses vs. vehicle of clinical score and AUC were performed by two-way ANOVA and two-tailed Student’s t -test, respectively ( n = 7 rats/group; mean ± s.e.m.). b Therapeutic efficacies of KSI-6666 (30 mg/kg/day) and FTY720 (3 mg/kg/day) in mouse EAE model. C57BL/6JJcl mice were immunized by the subcutaneous injection of myelin oligodendrocyte glycoprotein peptide (MOG 35–55 ), followed by the intraperitoneal injection of the pertussis toxin. The day after the first observation of clinical score 1 or above in each animal, oral administration of compounds once daily was started and lasted for 14 days. The clinical score and body weight were evaluated in each group. Statistical analyses vs. vehicle were performed by two-way ANOVA (control, n = 5 mice; KSI-6666, n = 5 mice; FTY720, n = 6 mice; mean ± s.e.m.). c Therapeutic efficacies of KSI-6666 (15 mg/kg/day) and KRP-203 (1.5 mg/kg/day) in the T-cell transfer colitis model. Isolated naive CD4 + CD45RB high T cells from BALB/cA mice were injected intraperitoneally into SCID mice and colitis was elicited. Two weeks after the transfer, twice daily oral administration of each compound was started and lasted for 14–16 days. Animals were sacrificed on the day after the final administration. Representative images of the histology were exhibited in left panels (scale bar = 100 µm). Colon weight, disease activity index (DAI) score, histological score, S100a9 mRNA expression level relative to ribosomal RNA expression, and % increase in body weight (between the day compound administration started and the end of the study) were evaluated in each group. Statistical analysis was performed by either two-tailed Student’s t -test or two-tailed Welch’s t -test according to F -test results (sham, n = 15 mice; control, n = 35 mice; KSI-6666, n = 16 mice; KRP-203, n = 21 mice; mean ± s.e.m.). Source data are provided as a Source Data file.
Article Snippet: EAE was induced in 9-week-old female C57BL/6JJcl mice using an EAE induction kit (Hooke Laboratories) according to the manufacturer’s protocol.
Techniques: Injection, Adjuvant, Two Tailed Test, Control, Isolation, Activity Assay, Expressing, RNA Expression
