Alpha-tocopherol succinate protects mice from gamma-radiation by induction of granulocyte-colony stimulating factor.
OBJECTIVE
The purpose of this study was to further elucidate the role of granulocyte-colony stimulating factor (G-CSF)-induced in response to alpha-tocopherol succinate (TS) administration in protecting mice from total body irradiation (TBI).


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 gamma-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 gamma-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.
Singh
Vijay K
VK
Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Bethesda, Maryland 20889-5603, USA. singh@afrri.usuhs.mil
Brown
Darren S
DS
Kao
Tzu-Cheg
TC
D000818:Animals; D001596:Benzylamines; D000080027:Cyclams; D005720:Gamma Rays; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D019650:Hematopoietic Stem Cell Mobilization; D006571:Heterocyclic Compounds / Q000494:pharmacology; D008297:Male; D051379:Mice; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D014916:Whole-Body Irradiation; D024502:alpha-Tocopherol / Q000494:pharmacology*
D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D011837:Radiation-Protective Agents; D016179:Granulocyte Colony-Stimulating Factor; D024502:alpha-Tocopherol; C088327:plerixafor