Trichostatin A ameliorated combined radiation and skin wound injury-induced mortality and hematopoietic suppression in a rat model

Effective countermeasure modalities against combined radiation injury, where the consequences of radiation exposure are highly complex with one or more conditions like burns, wounds, or infection, are yet far from reality. The current study aims to evaluate Trichostatin A (TSA), a presumptive radiomitigative molecule, in a rat model of combined radiation and wound injury (CRWI). Sprague-Dawley rats (200 ± 10 g) were whole-body exposed to different doses of 60Co-γ-irradiation (4-7Gy) alone and with an excision wound (EW, size 20 ± 2 mm diameter), to optimize CRWI radiation dose. The efficacy of TSA (75 ng/kg b.w.) was evaluated at LD50/30 CRWI dose, by administering intravenously in 2- and 5-doses, starting at 1 h post-irradiation and thereafter every 24 h to monitor 30-day survival, wound area, body weight, bacterial load, systemic changes, and histology. CRWI radiation dose-response curve rendered 5 Gy as LD50/30. Dose-dependent study of TSA showed that 5-doses and 2-doses rendered 83.3% and 50% survival respectively, against 50% survival after CRWI (5 Gy + EW). Treatment with TSA-5-doses resulted in 99% wound reduction (vs. 83% in CRWI); recovered CRWI-induced body weight loss, WBC, and platelets; ameliorated bacterial load in blood and skin wound; downregulated apoptosis (Bax expression) and cytotoxicity in bone marrow cells; reduced inflammation (TNF-α, IL-6, IL-1β), and normalized systemic histone deacetylase along-with restoration of structural changes in skin, bone marrow, and spleen. This study demonstrated that TSA substantially enhanced the survival of animals exposed to CRWI probably by ameliorating hematopoietic suppression and delayed wound healing.