Cell lines

Primary culture of hippocampal neurons

Preparation Method

Hippocampal primary neurons were treated with 50 μM and 10 μM FG-4592 for 72 h, starting from the second day in vitro. Microtubule-associated protein 2 (MAP2) staining and Western blotting were performed after cell collection.

Reaction Conditions

50 μM and 10 μM, 72h

Applications

FG-4592 promoted dendritic growth of primary hippocampal neurons in vitro.

Animal models

Wild-type C57BL/6 mice (10–12 weeks old, weighing 25–28 g)

Preparation Method

The FG-4592 was dissolved in DMSO at the concentration of 50 mg/ml and further diluted in PBS to 1 mg/ml. The mice were pretreated with FG-4592 for 48 h in FG-4592+Doxorubicin group at a dose of 10 mg/kg/day before Doxorubicin treatment.

Dosage form

10 mg/kg/day;intraperitoneal injection

Applications

FG-4592 rescued the reduction of LVEF and LVFS induced by Doxorubicin. FG-4592 obviously attenuated Doxorubicin-induced acute cardiac dysfunction and cardiomyocyte injury.

• CNS Neuroscience & Therapeutics (2022). PMID:35695696

FG-4592, as an oral bioavailable hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, can promote coordinated erythropoiesis through HIF-mediated transcription. FG-4592 was well tolerated and corrected anemia in incident HD and PD patients.^[1]

In vitro, treated with 10 μM or 50 μM FG-4592 in Primary Hippocampal Neurons, FG-4592 dose-dependently increased protein levels of HIF-1, and its target genes EPO and VEGF, as well as BDNF and PSD95.^[2]In vitro experiment it exhibited that treatment with 2, 10, and 20 μM FG-4592 dose-dependently reduced ROS generation and inflammation in LPS-stimulated BV-2 cells, a mouse microglia cell line, by inhibiting HIF-1α/NF-κB pathway.^[3]In HK-2 cells, treatment with 15 μM FG-4592 the injury induced by hypoxia remarkably ameliorated.^[5]

In vivo experiment it shown that treatment with 20 mg/kg/day FG-4592 intraperitoneally in Rat significantly affected body weight gain. In vivo efficacy it indicated that the high dose FG-4592 (20 mg/kg/day) could effectively reverse CUMS-induced depression-like behaviors.^[2]In vivo, mice were treated with 10 mg/kg FG-4592 intraperitoneally exhibited an improved renal function, compared with those without FG-4592 by biochemical and histological parameters.^[4]In C57BL/6 mice, treatment with 25.0 mg/kg FG-4592 intraperitoneally 24 and 2 h before irradiation, and then followed by total body irradiation of 8.5 Gy or local abdominal irradiation of 25.0 Gy could dramatically improve the survival rate of mice after IR.^[6]

References:
[1]Besarab A, Chernyavskaya E, Motylev I, Shutov E, Kumbar LM, Gurevich K, Chan DT, Leong R, et al. Roxadustat (FG-4592): Correction of Anemia in Incident Dialysis Patients. J Am Soc Nephrol. 2016 Apr;27(4):1225-33.
[2]Li G, et al. FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats. Neurotherapeutics. 2020 Apr;17(2):664-675.
[3]Yang DG, et al. Roxadustat alleviates nitroglycerin-induced migraine in mice by regulating HIF-1α/NF-κB/inflammation pathway. Acta Pharmacol Sin. 2022 Aug 10.
[4]Li X, et al. Pretreatment with Roxadustat (FG-4592) Attenuates Folic Acid-Induced Kidney Injury through Antiferroptosis via Akt/GSK-3β/Nrf2 Pathway. Oxid Med Cell Longev. 2020 Jan 20;2020:6286984.
[5]Miao AF, et al. Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against renal ischemia/reperfusion injury by inhibiting inflammation. Ren Fail. 2021 Dec;43(1):803-810.
[6]Feng Z, et al. FG-4592 protects the intestine from irradiation-induced injury by targeting the TLR4 signaling pathway. Stem Cell Res Ther. 2022 Jun 21;13(1):271.