Trichostatin A mitigates acute and late effects of radiation in intestine by regulation of DNA damage repair and Wnt/TGFβ/Smad signaling.

Abstract

Purpose: Radiation accidents and misuse of nuclear weapons elevate the risk of development of acute life-threatening injuries as well as their late effects are noted in survivors. Currently, no countermeasure agents are available for the management of radiation-induced GI injury (RIGI) in humans. In the present study, the radiomitigative potential of Trichostatin A (TSA) was evaluated against acute and late RIGI.

Methods: 15 Gy gamma radiation was delivered to the whole abdomen of C57BL/6 mice, followed by intravenous TSA (150 ng/kg) administration after 1 h and 24 h. Acute changes were checked 24 h and 3.5 days post irradiation. Mice were monitored for development of fibrosis, survival for 1 year and alteration in different signaling pathways.

Result: 15 Gy abdominal irradiation activated the DNA damage marker (γ-H2AX) by nearly 3.2 ± 0.29 fold and regulated the repair proteins, XRCC1 and PARP1 in the intestine, which was differentially regulated by TSA. The Wnt signaling pathway and stem cell proliferation in the intestine were also positively regulated by TSA. The TSA administered mice demonstrated improved intestinal morphology. 12.5% of TSA administered mice survived upto 1 year whereas 100% of 15 Gy exposed mice died by 6 months. The surviving mice that had received TSA showed reduced intestinal fibrosis than 15 Gy group, possibly via downregulation of TGFβ/Smad signaling.

Conclusion: The findings suggest that TSA have the potential to mitigate both acute and late effects of radiation in the intestine and can be explored as promising agent in the management of RIGI.