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Thiazolidinones reduce iron overload
Discussion
We report here that thiazolidinone derivatives 93, 165 and 156 manifested therapeutically important hepcidin- stimulatory activity, and the stimulatory effect on hep- cidin synthesis lasted for 3 to 4 days after a single dose in mice. No gross toxicity, systemic or hepatic inflammation, or histologically-detectable tissue toxicity was found fol- lowing acute or longer-term administration. Importantly, the three compounds greatly increased hepcidin concen- tration and relieved or prevented iron overload in two mouse models, Hfe-/- mice (representative of type 1 HH) and β-thalassemia intermedia mice, and prevented exces- sive iron deposition in organs of young Hfe-/- mice. Although Hfe-/- and β-thalassemic mice both exhibit a sim- ilar iron overload phenotype, the underlying molecular
AB
pathologies are different.41,42 The common mechanism is lower level of hepcidin compared to that in Wt mice, giv- ing rise to enhanced dietary iron uptake and iron egress out of macrophages and consequently iron deposition in various organs, especially the liver.36,43 However in β-tha- lassemias, unlike in HH, ineffective erythropoiesis and hemolysis accompany the iron overload, leading to enhanced erythrophagocytosis by macrophages in the spleen and consequently excess iron deposition in splenic macrophages.41 Upon treatment to relieve ineffective ery- thropoiesis, iron utilization for hemoglobin formation and erythropoiesis would be enhanced, resulting in reduced splenic iron overload.5,44 Our data showed significant reduction of splenic iron and spleen size/weight as well as improvement of hemoglobin and red blood cell indices in Hbbth3/+ mice after treatment with the compounds, demon-
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D
Figure 8. Compounds 93, 156 and 165 improved ineffective erythropoiesis in Hbbth3/+ mice. (A) Hemoglobin (HGB) content and (B) red blood cell (RBC) count in peripheral blood samples from 4-week old Hbbth3/+ mice following administration of compounds 93, 156 and 165 at a dose of 10 mg/kg body weight every other day for 2 weeks (n=3-4). (C) Blood smears (original magnification, ×1,000) with damaged or deformed erythrocytes indicated by arrows and (D) representative erythro- poiesis profiles of bone marrow cells from these mice (n=3-4). *P<0.05, compared to untreated, control (Ctrl) Hbbth3/+ mice.
haematologica | 2019; 104(9)
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