TP0463518 (TS-143) Ameliorates Peptidoglycan-Polysaccharide Induced Anemia of Inflammation in Rats.

ABSTRACT

TP0463518 (TS-143) is a competitive prolyl hydroxylase 1/2/3 pan-inhibitor, and has been shown to specifically stabilize hypoxia-inducible factor-2 alpha in the liver to increase erythropoietin production. While TP0463518 has been shown to improve renal anemia, its effect on anemia of inflammation is still unknown. In this study, we created a rat model of anemia of inflammation by administering peptidoglycan-polysaccharide (PG-PS) to Lewis rats; the PG-PS-treated rats developed anemia within 2 weeks after the PG-PS challenge. The hematopoietic effects of oral TP0463518 administration at 10 mg/kg once daily for 6 weeks were examined in this rat model. The hematocrit values in the TP0463518-treated group increased significantly from 32.8 ± 0.8 to 44.5 ± 2.1% after the treatment, which was comparable to that in the healthy control group. The change of the mean corpuscular volume following TP0463518 treatment was similar to that in the healthy control group up to week 4, and significantly higher than that in the vehicle-treated group. TP0463518 increased divalent metal transporter 1 and duodenal cytochrome b expressions in the intestine. Conversely, TP0465318 did not exert any effects on the expressions of genes involved in iron metabolism in the liver, even though TP0463518 dramatically increased erythropoietin expression. Furthermore, TP0463518 had no effect on the expressions of inflammation markers in the liver. These results suggest that TP0463518 increased iron absorption and improved anemia of inflammation without exacerbating liver inflammation. TP0463518 appears to have an acceptable safety profile and could become a useful new therapeutic option for anemia of inflammation.