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. 2013 Nov 1;54(6):1057-64.
doi: 10.1093/jrr/rrt077. Epub 2013 May 31.

Pharmaceutical drugs supporting regeneration of small-intestinal mucosa severely damaged by ionizing radiation in mice

Hiroshi Ishihara  1 , Izumi Tanaka, Haruko Yakumaru, Mika Tanaka, Kazuko Yokochi, Makoto Akashi
Affiliations

Pharmaceutical drugs supporting regeneration of small-intestinal mucosa severely damaged by ionizing radiation in mice

Hiroshi Ishihara et al. J Radiat Res. .

Abstract

Accidental exposure of the abdomen to high-dose radiation leads to severe consequences initiated by disruption of the mucosa in the small intestine. Therapeutic options are limited, even though various treatments have been investigated, particularly in the field of regenerative therapy. In order to identify readily available treatment methods, we included several current pharmaceutical drugs, for which the clinical trials have already been completed, in tests on mice that had undergone severe mucosal damage by radiation. The drugs were injected into mice 24 h after exposure to 15.7 Gy X-rays. The effects of the drugs on the damaged mucosa of the small intestine were evaluated using early regeneration indices [the expression of c-myb mRNA, and proliferation of epithelial cells in the form of microcolonies (MCs) by Days 4 and 5 post-irradiation] and the survival rate of the mice. Enhancement of mucosal regeneration at Day 4 (c-myb: P < 0.01, MC: P < 0.05) and improvement of the survival rate (P < 0.05) were observed when a clinical dose of gonadotropin, a stimulator of androgen, was injected. Similarly, a clinical dose of thiamazole (which prevents secretion of thyroid hormone) stimulated mucosal growth by Day 5 (c-myb: P < 0.01, MC: P < 0.05) and also improved the survival rate (P < 0.05). The nonclinical drugs histamine and high-dose octreotide (a growth hormone antagonist) also gave significant survival-enhancing benefits (P < 0.01 and P < 0.05, respectively). These results can be used to construct therapeutic programs and applied in various experimental studies to control the regeneration of damaged mucosa.

Keywords: anabolic steroid; glucagon; histamine; radiation accident; thyroid hormone.

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Figures

Fig. 1.
Fig. 1.
Damage and regeneration of the mucosa of the small intestine after a lethal dose of radiation. Proliferating mucosal epithelial cells with BrdU-incorporated nuclei (brown) were located in the middle of the crypts (before). After X-irradiation at 15.7 Gy, the proliferating cells in the crypts decreased each day (Day 1, Day 2), then disappeared (Day 3). Regeneration of the epithelium (as BrdU-positive microcolonies) was observed at Day 4. The size and the number of the microcolonies increased by Day 5.
Fig. 2.
Fig. 2.
Effect of drugs on the survival curve of mice exposed abdominally to 15.7 Gy of X-rays. Indicated drugs or saline (control, gray) were administered from Day 1 to Day 7 after the irradiation. (a) Comparison of glucagon (open square) as positive control, and gonadotropin (closed circle). (b) Effect of thyroxin (open downward triangle), or thiamazole (open upward triangle). (c) Effect of growth hormone (closed upward triangle), octreotide (closed downward triangle), histamine (closed square) or diphenhydramine (open diamond). P-values determined by log-rank test following the Kaplan-Meier method are indicated.
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