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

Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Bethesda, Maryland 20889-5603, USA.
International Journal of Radiation Biology (Impact Factor: 1.69). 01/2010; 86(1):12-21. DOI: 10.3109/09553000903264515
Source: PubMed


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).
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).
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.
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.

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Available from: Vijay K Singh, Mar 18, 2015
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    • "The possibility that radiation protective agents may implement their action by various routes and through different mechanisms mentioned above cannot be excluded. For example, indralin, a radioprotector with urgent action can act as a mitigator (Ilyin et al. 1994; Vasin et al. 2008a, [b], 2014b), while the radioprotector amifostine is capable of stimulating the antioxidant system of the body through the activation of Mn-SOD (Grdina et al. 2009), and the radiomodulator α-tocopherol succinate, at very high doses, possibly acting as a pro-oxidant, induces G-CSF mobilization (Singh et al. 2010). "
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    ABSTRACT: Purpose These comments suggest a division of radiation protective agents on the grounds of their mechanism of action that increase the radio resistance of an organism. Conclusion Given below is the division of radiation protective agents on the basis of their mechanism of action into 3 groups: 1) Radiation protective agents, with the implementation of radiation protective action taking place at the cellular level in the course of rapidly proceeding radiation-chemical reactions. At the same time, when the ionizing radiation energy is absorbed, these agents partially neutralize the “oxygen effect” as a radiobiological phenomenon, especially in the radiolysis of DNA; 2) Radiation protective agents that exert their effect at the system level by accelerating the post-radiation recovery of radiosensitive tissues through activation of a number of pro-inflammatory signaling pathways and an increase in the secretion of hematopoietic growth factors, including their use as mitigators in the early period after irradiation prior to the clinical development of acute radiation syndrome (ARS). 3) Radiomodulators including drugs and nutritional supplements that can elevate the resistance of the organism to adverse environmental factors, including exposure to ionization by means of modulating the gene expression through a hormetic effect of small doses of stressors and a “substrate” maintenance of adaptive changes, resulting in an increased antioxidant protection of the organism. Radiation protective agents having polyvalence in implementation of their action may simultaneously induce radioprotective effect by various routes with a prevalence of basis mechanisms of the action.
    SpringerPlus 08/2014; 3(1):414. DOI:10.1186/2193-1801-3-414
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    • "Drug preparation and administration TS (Sigma-Aldrich, St. Louis, MO) was administered as a suspension as described earlier (Singh et al. 2010a). For a 400 mg kg −1 dose (10 mg for a 25‐g mouse), 1,000 mg of TS was dispersed in 8.35 mL PEG‐400 and 0.5 mL Tween‐80 for a total volume of 10 mL. "
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    ABSTRACT: The authors demonstrate the efficacy of a bridging therapy in a preclinical animal model that allows the lymphohematopoietic system of severely immunocompromised individuals exposed to acute, high-dose ionizing irradiation to recover and to survive. CD2F1 mice were irradiated acutely with high doses causing severe, potentially fatal hematopoietic or gastrointestinal injuries and then transfused intravenously with progenitor-enriched, whole blood, or peripheral blood mononuclear cells from mice injected with tocopherol succinate- and AMD3100- (a chemokine receptor anatogonist used to improve the yield of mobilized progenitors). Survival of these mice over a 30-d period was used as the primary measured endpoint of therapeutic effectiveness. The authors demonstrate that tocopherol succinate and AMD3100 mobilize progenitors into peripheral circulation and that the infusion of mobilized progenitor enriched blood or mononuclear cells acts as a bridging therapy for lymphohematopoietic system recovery in mice exposed to whole-body ionizing irradiation. The results demonstrate that infusion of whole blood or blood mononuclear cells from tocopherol succinate (TS)- and AMD3100-injected mice improved the survival of mice receiving high radiation doses significantly. The efficacy of TS-injected donor mice blood or mononuclear cells was comparable to that of blood or cells obtained from mice injected with granulocyte colony-stimulating factor. Donor origin-mobilized progenitors were found to localize in various tissues. The authors suggest that tocopherol succinate is an optimal agent for mobilizing progenitors with significant therapeutic potential. The extent of progenitor mobilization that tocopherol succinate elicits in experimental mice is comparable quantitatively to clinically used drugs such as granulocyte-colony stimulating factor and AMD3100. Therefore, it is proposed that tocopherol succinate be considered for further translational development and ultimately for use in humans.
    Health physics 06/2014; 106(6):689-98. DOI:10.1097/HP.0000000000000089 · 1.27 Impact Factor
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    • "We also have reported that radiation exposure induces elevation of circulating G-CSF and that administering a neutralizing antibody to G-CSF exacerbates the deleterious effects of radiation exposure, suggesting that G-CSF induced in response to irradiation plays an important protective role in recovery (Singh et al., 2012d). Recently, we have demonstrated that the use of the G-CSF antibody abrogates the radioprotective efficacy of few radiation countermeasures (Singh et al., 2010; Kulkarni et al., 2013; Krivokrysenko et al., 2012; Grace et al., 2012). Our current study demonstrates that DT3 is a potent stimulator of several cytokines including G-CSF, and that the radioprotective efficacy of DT3 is mediated through G-CSF. "
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    ABSTRACT: The objective of this study was to determine the cytokine induction by delta tocotrienol (DT3, a promising radiation countermeasure) and to investigate the role of granulocyte colony-stimulating factor (G-CSF) in its radioprotective efficacy against ionizing radiation in mice. Multiplex Luminex was used to analyze DT3- and other tocols (gamma-tocotrienol and tocopherol succinate)-induced cytokines in CD2F1 mice. Mice were injected with an optimal dose of DT3 and a G-CSF antibody, and their 30-day survival against cobalt-60 gamma-irradiation was monitored. Neutralization of G-CSF by administration of a G-CSF-specific antibody in DT3-injected mice was investigated by multiplex Luminex. Our data demonstrate that DT3 induced high levels of various cytokines comparable to other tocols being developed as radiation countermeasures. DT3 significantly protected mice against ionizing radiation, and administration of a G-CSF neutralizing antibody to DT3-treated animals resulted in complete abrogation of DT3's radioprotective efficacy and neutralization of G-CSF in peripheral blood. Our study findings suggest that G-CSF induced by DT3 mediates its radioprotective efficacy against ionizing radiation in mice.
    Life sciences 01/2014; 98(2). DOI:10.1016/j.lfs.2014.01.065 · 2.70 Impact Factor
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