Mechanism of radioprotection by δ-tocotrienol: pharmacokinetics, pharmacodynamics and modulation of signalling pathways.
OBJECTIVE
The objective of this study was to investigate the correlation between in vivo δ-tocotrienol (DT3) pharmacokinetics, pharmacodynamics and radiation protection, and to evaluate the effect of DT3 pre-treatment on radiation-induced alterations in apoptotic and autophagic pathways.


METHODS
We evaluated pharmacokinetics (plasma, 0.5 to 12 h) and pharmacodynamics (peripheral blood indices; day 3, 7, 10 and 14) after a single subcutaneous injection of 300 mg kg(-1) DT3 in unirradiated CD2F1 mice. Next, we monitored 30-day post-irradiation survival (9.25 Gy) and haematopoietic recovery of DT3-treated mice (7 Gy) exposed to cobalt-60 γ-irradiation. The effects of DT3 on irradiated bone marrow apoptosis and autophagy were determined by analyses of key caspases (3, 7, 9 and 8), beclin-1 and light chain 3 conversion.


RESULTS
Plasma concentration of DT3 reached ∼195 µM (Cmax) 1 h after injection (Tmax), and DT3 was eliminated from plasma 12 h later. In unirradiated mice, DT3 significantly increased white blood cells (WBCs), neutrophils, lymphocytes (day 3 post DT3 injection) and platelets (day 7) by 1.5- to 2-fold, over vehicle-treated control. DT3 pre-treatment improved 30-day survival to 100% (∼15% in control) and accelerated recovery of reticulocytes, platelets, WBCs, neutrophils, lymphocytes and monocytes in peripheral blood. DT3 reduced activation of caspase-8, caspase-3 and caspase-7, inherent to apoptosis, while increasing autophagy-related beclin-1 expression in irradiated bone marrow.


CONCLUSIONS
These data indicate that DT3 stimulates multilineage haematopoiesis, protects against radiation-induced apoptosis downstream of the mitochondria and stimulates cytoprotective autophagy. Apart from a potent antioxidant activity, DT3 may elicit survival advantage following irradiation by enhancing haematopoiesis and modulating signalling pathways.
Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA. satyamitra@afrri.usuhs.mil
M
M
Satyamitra
P
P
Ney
J
J
Graves
C
C
Mullaney
V
V
Srinivasan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001853:Bone Marrow / Q000187:drug effects / Q000528:radiation effects; D020169:Caspases / Q000378:metabolism / Q000528:radiation effects; D002851:Chromatography, High Pressure Liquid; D045304:Cytochromes c / Q000378:metabolism / Q000528:radiation effects; D004906:Erythrocyte Count; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D010198:Pancytopenia / Q000188:drug therapy; D010976:Platelet Count; D011837:Radiation-Protective Agents / Q000032:analysis / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
D011837:Radiation-Protective Agents; D014810:Vitamin E; C082097:tocotrienol, delta; D045304:Cytochromes c; D020169:Caspases