Effects of Gamma-Tocotrienol on Partial-Body Irradiation-Induced Intestinal Injury in a Nonhuman Primate Model

Abstract

Exposure to high doses of radiation, accidental or therapeutic, often results in gastrointestinal (GI) injury. To date, there are no therapies available to mitigate GI injury after radiation exposure. Gamma-tocotrienol (GT3) is a promising radioprotector under investigation in nonhuman primates (NHP). We have shown that GT3 has radioprotective function in intestinal epithelial and crypt cells in NHPs exposed to 12 Gy total-body irradiation (TBI). Here, we determined GT3 potential in accelerating the GI recovery in partial-body irradiated (PBI) NHPs using X-rays, sparing 5% bone marrow. Sixteen rhesus macaques were treated with either vehicle or GT3 24 h prior to 12 Gy PBI. Structural injuries and crypt survival were examined in proximal jejunum on days 4 and 7. Plasma citrulline was assessed using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Crypt cell proliferation and apoptotic cell death were evaluated using Ki-67 and TUNEL staining. PBI significantly decreased mucosal surface area and reduced villous height. Interestingly, GT3 increased crypt survival and enhanced stem cell proliferation at day 4; however, the effects seemed to be minimized by day 7. GT3 did not ameliorate a radiation-induced decrease in citrulline levels. These data suggest that X-rays induce severe intestinal injury post-PBI and that GT3 has minimal radioprotective effect in this novel model.

Increased response to immune checkpoint inhibitors with dietary methionine restriction

“…To evaluate PD-L1, CD8, and MHC-1 expression in formalin-fixed paraffin-embedded tissue sections of mouse tumors, immunohistochemical staining was performed with conventional techniques using an avidin-biotin complex, diaminobenzidine chromogen, and hematoxylin counterstaining (26). Sections (4 µm thick) were deparaffinized, rehydrated and blocked for endogenous peroxidase, followed by incubation with rabbit anti-PD-L1 (64988, 1:100, Cell Signaling Technology), rat anti-CD8 (14-0808-80, 1:50, Invitrogen, Waltham, MA) and rabbit anti-MHC-1 (NBP3-09017, 1:50, Novus Biologicals, Centennial, CO) overnight at 4ºC.…”

Development of radiation countermeasure agents for acute radiation syndromes

“…For example, several studies have shown that γ-tocotrienol (γGT3), a saturated vitamer of vitamin E, exerts protective effects on hematopoietic stem cells and intestinal crypt cells in the gastrointestinal tract in murine and nonhuman primate (NHP) models, accelerating recovery from IR-induced injury at various doses (5.8, 6.5, 11, or 12 Gy). [24][25][26][27][28][29][30][31] The radioprotector, indralin (B-190), was also shown to exhibit radioprotective effects on hematopoietic and other tissues, including the intestines, skin, testes, and salivary glands, and it improved survival rates in monkeys after total-body irradiation (TBI) at a dose of 6.8 Gy. [32][33][34][35][36] BIO300, a suspension of synthetic genistein nanoparticles, was developed by the Humanetics Corporation to prevent and mitigate the effects of ARS and DEARE, and radioprotective effects have been demonstrated in mice and NHPs.…”

“…Some antioxidants are being investigated as radioprotective agents for ARS. For example, several studies have shown that γ‐tocotrienol (γGT3), a saturated vitamer of vitamin E, exerts protective effects on hematopoietic stem cells and intestinal crypt cells in the gastrointestinal tract in murine and nonhuman primate (NHP) models, accelerating recovery from IR‐induced injury at various doses (5.8, 6.5, 11, or 12 Gy) 24–31 . The radioprotector, indralin (B‐190), was also shown to exhibit radioprotective effects on hematopoietic and other tissues, including the intestines, skin, testes, and salivary glands, and it improved survival rates in monkeys after total‐body irradiation (TBI) at a dose of 6.8 Gy 32–36 .…”

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation

“…In addition to HSCs and HPCs, GT3 reduced radiation-induced persistent DNA damage of lymphoid/myeloid progenitor cells, while significantly inducing G-CSF (granulocyte-colony stimulating factor), a crucial factor in stem cell mobilization and hematopoietic recovery (36,37). Interestingly, GT3 also demonstrated its radioprotective role in intestinal epithelial and crypt cells in an NHP model exposed to a supralethal dose of radiation (38,39). Most importantly, GT3 is under advanced development as a radioprotective MCM following the U.S. FDA Animal Rule to be used as a pre-exposure prophylaxis for H-ARS (31).…”