A Combination of Pre- and Post-Exposure Ascorbic Acid Rescues Mice from Radiation-Induced Lethal Gastrointestinal Damage

Abstract

The development of an effective therapy for radiation-induced gastrointestinal damage is important, because it is currently a major complication of treatment and there are few effective therapies available. Although we have recently demonstrated that pretreatment with ascorbic acid attenuates lethal gastrointestinal damage in irradiated mice, more than half of mice eventually died, thus indicating that better approach was needed. We then investigated a more effective therapy for radiation-induced gastrointestinal damage. Mice receiving abdominal radiation at 13 Gy were orally administered ascorbic acid (250 mg/kg/day) for three days before radiation (pretreatment), one shot of engulfment (250 mg/kg) at 8 h before radiation, or were administered the agent for seven days after radiation (post-treatment). None of the control mice survived the abdominal radiation at 13 Gy due to severe gastrointestinal damage (without bone marrow damage). Neither pretreatment with ascorbic acid (20% survival), engulfment (20%), nor post-treatment (0%) was effective in irradiated mice. However, combination therapy using ascorbic acid, including pretreatment, engulfment and post-treatment, rescued all of the mice from lethal abdominal radiation, and was accompanied by remarkable improvements in the gastrointestinal damage (100% survival). Omitting post-treatment from the combination therapy with ascorbic acid markedly reduced the mouse survival (20% survival), suggesting the importance of post-treatment with ascorbic acid. Combination therapy with ascorbic acid may be a potent therapeutic tool for radiation-induced gastrointestinal damage.

Epicatechin as a promising agent to countermeasure radiation exposure by mitigating mitochondrial damage in human fibroblasts and mouse hematopoietic cells

“…The in vivo radioprotective properties of AA have been well demonstrated in several reports (3)(4)(5). In the present study, the in vivo radioprotective effects of EC in mouse blood cells were investigated.…”

“…Postradiation treatment with ascorbic acid (AA) is reportedly effective in mitigating radiation lethality in mice after whole body irradiation at 7.5 Gy (3). In addition, radiation-induced lethal gastrointestinal damage as well as radiation injury to bone marrow cells were reduced by treatment with AA ABBREVIATIONS: DCm, mitochondrial membrane potential; AA, ascorbic acid; ATM, ataxia telangiectasia mutated; DCFDA, 2',7'-dichlorofluorescin diacetate; DSB, double-strand break; EC, epicatechin; H2AX, H2A histone family, member X; IR, ionizing radiation; mtDNA, mitochondrial DNA; NAC, N-acetyl-L-cysteine; Nrf2, nuclear factor erythroid 2-related factor 2; oxphos, oxidative phosphorylation; ROS, reactive oxygen species; SOD, superoxide dismutase; Tempo, 2,2,6,6-tetramethyl-1-piperidinyloxy; TOC, a-tocophenol; WBC, white blood cell; WT, wild type (4,5). Epicatechin (EC), a component of green tea extract, is reported to scavenge radiation-induced reactive oxygen species (ROS) and has a radioprotective effect in human cells as well as biologic models of zebrafish and mice (6)(7)(8)(9).…”

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer

“…Addition of pharmacological ascorbate partially reversed the decreases in both the 10 Gy and 13 Gy groups of mice suggesting that ascorbate may protect the gastrointestinal tract from the damaging effects of IR. Additionally, previous studies have demonstrated that radiation-induced jejunal toxicity was accompanied by increases in serum tumor necrosis factor-α (TNF-α) ( 34 ). TNF-α was 7.5 ± 2.2 pg/ml in controls and was increased to 25.0 ± 1.5 pg/ml after 13 Gy.…”

Gastroduodenal mucosal defense

“…Ito et al studied the effects of ascorbic acid administration in preventing RIGD in mice, reporting that administration of ascorbic acid 3 days prior to radiation exposure, followed by another dose 8 hours before exposure, followed by continued administration for 7 days after radiation exposure was associated with a 100% survival rate. This compared to a maximum of 20% survival rate in mice treated with ascorbic acid 3 days prior to radiation exposure, those treated with a single dose 8 hours before exposure or those treated post-exposure [4]. Blockade of p53 is not a viable strategy for prevention of RIGD since p53 maintains genomic stability.…”