Alpha-tocopherol succinate protects mice from gamma-radiation by induction of granulocyte-colony stimulating factor

Abstract

Purpose: The purpose of this study was to further elucidate the role of granulocyte-colony stimulating factor (G-CSF)-induced in response to α-tocopherol succinate (TS) administration in protecting mice from total body irradiation (TBI).

Material and methods: The dose, route, and schedule of TS administration for optimal G-CSF induction were determined by giving TS through subcutaneous (sc) and oral routes to male CD2F1 mice. The level of cytokine in serum was determined by multiplex Luminex. The role of G-CSF on survival after TBI was determined by first treating mice with a protective dose (400 mg/kg) of TS 24 h before exposure to a lethal dose (9.2 Gy, 0.6 Gy/min) of cobalt-60 γ-irradiation. The treated mice were then given neutralising antibody to G-CSF 16 h before TBI to abrogate the radioprotective efficacy of TS. The efficacy of whole blood samples obtained from TS-treated mice was evaluated to protect naïve lethally irradiated mice. The hematopoietic stem cells in blood from TS-treated mice were analysed by fluorescence-activated cell sorting (FACS).

Results: Maximal levels of G-CSF were observed in peripheral blood 24 h after sc administration of TS. When TS-treated mice were given neutralising antibody to G-CSF, TS failed to protect against TBI. After being challenged with an LD90/30 (lethal dose causing 90% mortality over 30 days) dose of γ-radiation, mice infused with whole blood from TS- and AMD3100 (1,1′-{1,4-phenylenebis(methylene)}bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride)-treated mice exhibited significantly higher survival compared with those infused with whole blood from vehicle-injected mice. FACS data revealed that hematopoietic stem cells were mobilised into the peripheral blood.

Conclusions: The results indicate that G-CSF-induced by the administration of TS, mobilises hematopoietic stem cells and is responsible for the protection from ionising radiation.

Keywords:

• cytokines
• gamma irradiation
• granulocyte colony stimulating factor
• mice
• neutralising antibody
• radioprotection
• stem cells
• tocopherol succinate

Acknowledgements

The authors thank the Veterinary and Radiation Sciences Department staff for their technical and laboratory assistance, and Margaret L. Kehl, Oluseyi Fatanmi, Vaishali Parekh, and Stephen Wise for expert technical assistance. The authors are also thankful to Professor Terry C. Pellmar and Dr Mark H. Whitnall for their helpful discussions. This work was supported by intramural research project RAB2CZ.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.