Abstract
BackgroundOur previous research demonstrated that one subcutaneous injection of 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) 24 hours (h) before irradiation (8.75 Gy) increased mouse survival by 75%. However, the protective mechanism of 17-DMAG is currently unknown. The present study aimed to investigate whether oral administration of 17-DMAG was also radioprotective and the potential role it may play in radioprotection.ResultsA single dose of orally pre-administered (24, 48, or 72 h) 17-DMAG (10 mg/kg) increased irradiated mouse survival, reduced body weight loss, improved water consumption, and decreased facial dropsy, whereas orally post-administered 17-DMAG failed. Additional oral doses of pre-treatment did not improve 30-day survival. The protective effect of multiple pre-administrations (2−3 times) of 17-DMAG at 10 mg/kg was equal to the outcome of a single pre-treatment. In 17-DMAG-pretreated mice, attenuation of bone marrow aplasia in femurs 30 days after irradiation with recovered expressions of cluster of differentiation 34, 44 (CD34, CD44), and survivin in bone marrow cells were observed. 17-DMAG also elevated serum granulocyte-colony stimulating factor (G-CSF), decreased serum fms-related tyrosine kinase 3 ligand, and reduced white blood cell depletion. 17-DMAG ameliorated small intestinal histological damage, promoted recovery of villus heights and intestinal crypts including stem cells, where increased leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) was found 30 days after irradiation.Conclusions17-DMAG is a potential radioprotectant for bone marrow and small intestine that results in survival improvement.
Highlights
MethodsAnimals Male CD2F1 mice were purchased from Harlan Laboratories (Dublin, VA, USA) and used at age of 10 to 12 weeks at the time of irradiation
Our previous research demonstrated that one subcutaneous injection of 17-Dimethylaminoethylamino-17demethoxygeldanamycin (17-DMAG) 24 hours (h) before irradiation (8.75 Gy) increased mouse survival by 75%
In vehicle-treated mice, radiation-induced mortality started at day 9 after irradiation and the 30-day survival was 33.5% (Figure 1A)
Summary
Animals Male CD2F1 mice were purchased from Harlan Laboratories (Dublin, VA, USA) and used at age of 10 to 12 weeks at the time of irradiation. The mice were housed in groups of four in polycarbonate microisolator cages (11.5 × 7.5 × 5 in.) with filter tops on autoclaved rodent hardwood bedding. Animal rooms were maintained at 21 ± 2°C, 50% ± 10% humidity, and 12-h light/dark cycle. All facilities were accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. Rodent food (Harlan Teklad Rodent Diet 8604) and water were freely available for mice. All handling procedures were performed in compliance with guidelines from the National Research Council, and were approved by the Institutional Animal Care and Use Committee (IACUC) of the AFRRI
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