Pretreatment with Ascorbic Acid Prevents Lethal Gastrointestinal Syndrome in Mice Receiving a Massive Amount of Radiation
Pretreatment with Ascorbic Acid Prevents Lethal Gastrointestinal Syndrome in Mice Receiving a Massive Amount of Radiation
Original study authors:
Yamamoto T, Kinoshita M, Shinomiya N, Hiroi S, Sugasawa H, Matsushita Y, Majima T, Saitoh D, Seki S.
Abstract:
While bone marrow or stem cell transplantation can rescue bone marrow aplasia in patients accidentally exposed to a lethal radiation dose, radiation-induced irreversible gastrointestinal damage (GI syndrome) is fatal. We investigated the effects of ascorbic acid on radiation-induced GI syndrome in mice. Ascorbic acid (150 mg/kg/day) was orally administered to mice for 3 days, and then the mice underwent whole body irradiation (WBI). Bone marrow transplantation (BMT) 24 h after irradiation rescued mice receiving a WBI dose of less than 12 Gy. No mice receiving 14 Gy-WBI survived, because of radiation-induced GI syndrome, even if they received BMT. However, pretreatment with ascorbic acid significantly suppressed radiation-induced DNA damage in the crypt cells and prevented denudation of intestinal mucosa; therefore, ascorbic acid in combination with BMT rescued mice after 14 Gy-WBI. DNA microarray analysis demonstrated that irradiation up-regulated expressions of apoptosis-related genes in the small intestine, including those related to the caspase-9-mediated intrinsic pathway as well as the caspase-8-mediated extrinsic pathway, and down-regulated expressions of these genes in ascorbic acid-pretreated mice. Thus, pretreatment with ascorbic acid may effectively prevent radiation-induced GI syndrome.
Objective:
Biomedical problems caused by radiation accidents still remain a grave concern, because we cannot rescue most of the patients exposed to critical radiation doses. After a high-dose radiation exposure, patients usually suffer from fatal damage to multiple organs, which has been referred to collectively as acute radiation syndrome.
Bone marrow failure is the most common complication after acute radiation exposure, causing severe pancytopenia, which results in fatal immune dysfunction. Since the early 1950’s, bone marrow transplantation (BMT) has been utilized for the reconstitution of damaged bone marrow, and recently, a more sophisticated technique, the transplantation of umbilical cord blood cells, has been developed. Such advanced therapeutic interventions effectively rescue patients from bone marrow failure caused by fatal irradiation. However, another complication has emerged among patients initially successfully rescued by stem cell transplantation, and that is radiation-induced gastrointestinal (GI) syndrome.
DESIGN:
The mice were exposed to 6 to 14 Gy whole body irradiation (WBI), given at a dose rate of 0.45 Gy/min at 150 kV and 5 mA
Ascorbic acid was dissolved in distilled water and administered per os (p.o.) to mice at 150 mg/kg/day for 3 days before or after irradiation. Control mice received p.o. distilled water only.
Mice were given bone marrow transplantation after the irradiation
RESULTS:
BMT could not save mice after 14 Gy whole body irradiation (WBI)
Treatment with ascorbic acid before but not after radiation dramatically improved mouse survival after 14 Gy WBI in combination with BMT
Pretreatment with ascorbic acid before 14 Gy WBI dramatically improved mouse survival (42% survival), whereas treatment with ascorbic acid after radiation did not affect survival (no mice survived).
The rescued mice that were pretreated with ascorbic acid and received BMT after 14 Gy WBI were healthy 30 days after radiation, although they showed marked radiation-induced depigmentation in the fur.
Oral intake of ascorbic acid for 12 h before 14 Gy WBI induced a substantial effect on survival of mice with GI syndrome
The intake of ascorbic acid only at 12 h improved mortality, comparable to mortality seen by ascorbic acid intake for 3 days (both treatments for 12 h and 3 days showed 42% survival).
CONCLUSIONS:
Treatment with ascorbic acid after radiation exposure could not rescue mice from lethal GI syndrome, even if they received BMT. Therefore, it may be important to maintain high tissue concentrations of ascorbic acid before and at the time of radiation exposure, because DNA damage occurs during exposure. It is notable that oral intake for only 12 h might be sufficient to cause the ascorbic acid therapeutic effect, suggesting that if a mouse orally receives a substantial amount of ascorbic acid one time, the GI syndrome is prevented. Therefore, when we undertake the rescue of victims from a radiation-contaminated area just after a radiation accident or terrorism, it is important for rescue team members to promptly take ascorbic acid orally.
Yamamoto T, Kinoshita M, Shinomiya N, Hiroi S, Sugasawa H, Matsushita Y, Majima T, Saitoh D, Seki S. Pretreatment with Ascorbic Acid Prevents Lethal Gastrointestinal Syndrome in Mice Receiving a Massive Amount of Radiation. J Radiat Res (Tokyo). 2009 Dec 4. [Epub ahead of print] PubMed PMID: 19959877
Discussion:
The study clearly shows that for minimising radiation side effects, PRETREATMENT with Vitamin C is essential. The oral doses given to these mice relate to approx 10g per day for humans.
A similar situation can be found with mercury toxicity - pretreatment of animals with vitamin C protects them from lethal doses of mercury (MOKRANJAC M, PETROVIC C. [VITAMIN C AS ANTIDOTE IN CASES OF POISONING BY FATAL DOSES OF MERCURY.] C R Hebd Seances Acad Sci. 1964 Jan 27;258:1341-2. French. PMID: 14133923).
Higher plasma and tissue levels of ascorbate can be achieved with IV ascorbate. Although studies have not been conducted comparing oral vs. IV ascorabte pretreatment at various doses, it is prudent to be aware of the potential for greater impact and protection by ascorbate if it is given IV.
