Pentoxifylline Enhances the Radioprotective Properties of γ-Tocotrienol: Differential Effects on the Hematopoietic, Gastrointestinal and Vascular Systems

Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Radiation Research (Impact Factor: 2.91). 03/2011; 175(3):297-306. DOI: 10.1667/RR2399.1
Source: PubMed

ABSTRACT The vitamin E analog γ-tocotrienol (GT3) is a potent radioprotector and mitigator. This study was performed to (a) determine whether the efficacy of GT3 can be enhanced by the addition of the phosphodiesterase inhibitor pentoxifylline (PTX) and (b) to obtain information about the mechanism of action. Mice were injected subcutaneously with vehicle, GT3 [400 mg/kg 24 h before total-body irradiation (TBI)], PTX (200 mg/kg 30 min before TBI), or GT3+PTX before being exposed to 8.5-13 Gy TBI. Overall lethality, survival time and intestinal, hematopoietic and vascular injury were assessed. Cytokine levels in the bone marrow microenvironment were measured, and the requirement for endothelial nitric oxide synthase (eNOS) was studied in eNOS-deficient mice. GT3+PTX significantly improved survival compared to GT3 alone and provided full protection against lethality even after exposure to 12.5 Gy. GT3+PTX improved bone marrow CFUs, spleen colony counts and platelet recovery compared to GT3 alone. GT3 and GT3+PTX increased bone marrow plasma G-CSF levels as well as the availability of IL-1α, IL-6 and IL-9 in the early postirradiation phase. GT3 and GT3+PTX were equally effective in ameliorating intestinal injury and vascular peroxynitrite production. Survival studies in eNOS-deficient mice and appropriate controls revealed that eNOS was not required for protection against lethality after TBI. Combined treatment with GT3 and PTX increased postirradiation survival over that with GT3 alone by a mechanism that may depend on induction of hematopoietic stimuli. GT3+PTX did not reduce GI toxicity or vascular oxidative stress compared to GT3 alone. The radioprotective effect of either drug alone or both drugs in combination does not require the presence of eNOS.

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Available from: Martin Hauer-Jensen, Sep 28, 2015
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    • "The increasing levels of GT3 in these tissues may be due to these two organs having the advantage to re-uptake GT3 from plasma after release from adipose tissue. Actually, as a radioprotector, GT3 has strong beneficial effects on the cardiovascular system and spleen colony formation [22]. For bone tissues (femur and spine), the GT3 level was relatively stable and had no significant change (P > 0.05) from day 3 to day 14 after administration (Figure 2). "
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    ABSTRACT: gamma-tocotrienol (GT3), an analogue of vitamin E, has gained increasing scientific interest recently as it provides significant health benefits. It has been shown that emulsified GT3, after subcutaneous administration, has long-term biological effects. However, whether the effects are due to the increase of GT3 level in the early phase following administration or the persistent functions after accumulation in tissues is unknown. This study was conducted to determine the levels of GT3 in different tissues by high performance liquid chromatography (HPLC) with a fluorescence detector after a single-dose of GT3 with polyethylene glycol (PEG-400) emulsion via subcutaneous injection. Previous studies have explored that GT3 has favorable effects on bone and can inhibit osteoclast formation. To confirm the persistent biological activity of accumulated GT3 in tissues, receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) gene expressions, which have an important role in regulating osteoclast formation, were also evaluated in bone tissue on day 1, 3, 7 and 14 after a signal subcutaneous injection of GT3. C57BL/6 female mice were administrated GT3 (100mg/kg body weight) with PEG-400 emulsion by subcutaneous injection. GT3 levels in different tissues were determined by HPLC with a fluorescence detector. Gene expressions were measured by real-time PCR. GT3 predominantly accumulated in adipose and heart tissue, and was maintained at a relatively stable level in bone tissues after a single-dose administration. Accumulated GT3 in bone tissues significantly inhibited the increase in RANKL expression and the decrease in OPG expression induced by db-cAMP. We investigated the tissue distribution of GT3 with PEG emulsion by subcutaneous administration, which has never been reported so far. Our results suggest that GT3 with PEG emulsion accumulated in tissues is able to carry out a long-term biological effect and has therapeutic value for treating and preventing osteoporosis.
    Lipids in Health and Disease 04/2014; 13(1):66. DOI:10.1186/1476-511X-13-66 · 2.22 Impact Factor
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    • "It is possible that GTDMG induces radioprotective cytokines such as G-CSF and growth factors in the way that alpha-tocopherol succinate does [41], although as yet we do not have experimental data to support this. Several other mechanisms have been considered to explain the effect of tocopherols, tocotrienols and their derivatives in their action as radiation countermeasures [33, 35–37, 42, 43]. One such mechanism is based on the antioxidant property. "
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    ABSTRACT: We examined the radioprotective and mitigative effects of gamma-tocopherol-N,N-dimethylglycine ester (GTDMG), a novel water-soluble gamma-tocopherol derivative, against X-irradiation-induced bone marrow death in mice. Mice (C3H, 10 weeks, male) were injected intraperitoneally with GTDMG suspended in a 0.5% methyl cellulose solution before or after receiving of 7.5-Gy whole body X-irradiation. GTDMG significantly enhanced the 30-day survival rate when given 30 min before or immediately after the irradiation. Its mitigative activity (administered after exposure) was examined further in detail. The optimal concentration of GTDMG given immediately after irradiation was around 100 mg/kg body weight (bw) and the 30-day survival rate was 97.6 ± 2.4%. When GTDMG was administered 1, 10 and 24 h post-irradiation, the survival rate was 85.7 ± 7.6, 75.0 ± 9.7 and 36.7 ± 8.8%, respectively, showing significant mitigation even at 24 h after irradiation (P < 0.05). The value of the dose reduction factor (100 mg/kg bw, given intraperitoneally (i.p.) immediately after irradiation) was 1.25. GTDMG enhanced the recovery of red blood cell-, white blood cell-, and platelet-counts after irradiation and significantly increased the number of endogenous spleen colonies (P < 0.05). Subcutaneous (s.c.) administration also had mitigative effects. In conclusion, GTDMG is a potent radiation mitigator.
    Journal of Radiation Research 08/2013; 55(1). DOI:10.1093/jrr/rrt094 · 1.80 Impact Factor
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    • "In addition, γ- and δ-tocotrienols may mediate their protective effects in radiation injury in part by inhibition of 3-hydroxy-3-methyl-glutaryl-CoA reductase [18,22,23]. PTX enhanced the radioprotective properties of γ-tocotrienol in a combined administration before whole body irradiation [24]. "
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    ABSTRACT: Radiation-induced heart disease (RIHD) is a long-term side effect of radiotherapy of intrathoracic, chest wall and breast tumors when radiation fields encompass all or part of the heart. Previous studies have shown that pentoxifylline (PTX) in combination with α-tocopherol reduced manifestations of RIHD in rat models of local heart irradiation. The relative contribution of PTX and α-tocopherol to these beneficial effects are not known. This study examined the effects of PTX alone or in combination with tocotrienols, forms of vitamin E with potential potent radiation mitigation properties. Rats received localized X-irradiation of the heart with an image-guided irradiation technique. At 3 months after irradiation rats received oral treatment with vehicle, PTX, or PTX in combination with a tocotrienol-enriched formulation. At 6 months after irradiation, PTX-treated rats showed arrhythmia in 5 out of 14 animals. PTX alone or in combination with tocotrienols did not alter cardiac radiation fibrosis, left ventricular protein expression of the endothelial markers von Willebrand factor and neuregulin-1, or phosphorylation of the signal mediators Akt, Erk1/2, or PKCα. On the other hand, tocotrienols reduced cardiac numbers of mast cells and macrophages, but enhanced the expression of tissue factor. While this new rat model of localized heart irradiation does not support the use of PTX alone, the effects of tocotrienols on chronic manifestations of RIHD deserve further investigation.
    PLoS ONE 07/2013; 8(7):e68762. DOI:10.1371/journal.pone.0068762 · 3.23 Impact Factor
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