Gamma-tocotrienol, a radiation countermeasure, reverses proteomic changes in serum following total-body gamma irradiation in mice

Abstract

Radiological incidents or terrorist attacks would likely expose civilians and military personnel to high doses of ionizing radiation, leading to the development of acute radiation syndrome. We examined the effectiveness of prophylactic administration of a developmental radiation countermeasure, γ-tocotrienol (GT3), in a total-body irradiation (TBI) mouse model. CD2F1 mice received GT3 24 h prior to 11 Gy cobalt-60 gamma-irradiation. This dose of radiation induces severe hematopoietic acute radiation syndrome and moderate gastrointestinal injury. GT3 provided 100% protection, while the vehicle control group had 100% mortality. Two-dimensional differential in-gel electrophoresis was followed by mass spectrometry and Ingenuity Pathway Analysis (IPA). Analysis revealed a change in expression of 18 proteins in response to TBI, and these changes were reversed with prophylactic treatment of GT3. IPA revealed a network of associated proteins involved in cellular movement, immune cell trafficking, and inflammatory response. Of particular interest, significant expression changes in beta-2-glycoprotein 1, alpha-1-acid glycoprotein 1, alpha-2-macroglobulin, complement C3, mannose-binding protein C, and major urinary protein 6 were noted after TBI and reversed with GT3 treatment. This study reports the untargeted approach, the network, and specific serum proteins which could be translated as biomarkers of both radiation injury and protection by countermeasures.

Analysis of the Proteomic Profile in Serum of Irradiated Nonhuman Primates Treated with Ex-Rad, a Radiation Medical Countermeasure

“…Although there was a significant overlap in the pathways that reverted to homeostasis with both dosing regimens, radiation-induced perturbations in a greater number of proteins were significantly restored by the treatment schedule of Ex-Rad II (48 and 60 h post-irradiation of Ex-Rad administration) compared to Ex-Rad I (24 and 36 h post-irradiation Ex-Rad administration). Recently, we have demonstrated restoration of irradiation-induced proteomic alterations using a few promising radiation MCMs under development; gamma-tocotrienol, tocopherol succinate, and BIO 300 in murine and NHP models. ,, There is another report demonstrating a robust alteration by gamma-tocotrienol in spleen proteomic profiles including upregulation of the Wnt signaling pathway and actin-cytoskeleton linked proteins in mediating the radiation injury in mice, which suggests that pretreatment with gamma-tocotrienol attenuated radiation-induced injury in the spleen by modulating various cell signaling proteins . This current study also confirms the restoration of radiation-induced proteomic alterations by Ex-Rad treatment, albeit by different mechanistic pathways.…”

“…Recently, we have demonstrated restoration of irradiation-induced proteomic alterations using a few promising radiation MCMs under development; gamma-tocotrienol, 38 tocopherol succinate, 39 and BIO 300 40 in murine and NHP models. 36,41,42 There is another report demonstrating a robust alteration by gamma-tocotrienol in spleen proteomic profiles including upregulation of the Wnt signaling pathway and actin-cytoskeleton linked proteins in mediating the radiation injury in mice, which suggests that pretreatment with gamma-tocotrienol attenuated radiationinduced injury in the spleen by modulating various cell signaling proteins. 43 This current study also confirms the restoration of radiation-induced proteomic alterations by Ex-Rad treatment, albeit by different mechanistic pathways.…”

Nuclear and Radiological Emergencies: Biological Effects, Countermeasures and Biodosimetry

“…In this regard, the efficacy of tocotrienols is attributed to their higher antioxidant potential, their ability to inhibit HMG-CoA reductase activity [ 185 ], and increase TM expression in endothelial cells [ 186 ], which result in anti-permeability, anti-inflammatory and anti-thrombotic response [ 179 ]. Promising radioprotective results of γ-tocotrienol (GT3) have been demonstrated in mice [ 187 ] and primate models, by preserving the hematopoietic stem and progenitor cells, and recovery from γ-irradiation (5.8 or 6.5 Gy)-induced neutropenia and thrombocytopenia [ 188 , 189 ]. Recent preclinical studies evidenced that GT3 may be a potential countermeasure against late degenerative tissue effects of high-LET radiation in the heart [ 190 ] and lung radiation injury [ 191 ].…”

Lung transcriptome of nonhuman primates exposed to total- and partial-body irradiation

“… 21 Recently, we have demonstrated that GT3 restores radiation-induced proteomic changes in irradiated murine (11 Gy, LD 100/30 ). 37 In the current study we have used a supralethal dose of radiation, which may be responsible for limited transcriptomic changes by GT3.…”