Nicaraven Attenuates Radiation-Induced Injury in Hematopoietic Stem/Progenitor Cells in Mice

Abstract

Nicaraven, a chemically synthesized hydroxyl radical-specific scavenger, has been demonstrated to protect against ischemia-reperfusion injury in various organs. We investigated whether nicaraven can attenuate radiation-induced injury in hematopoietic stem/progenitor cells, which is the conmen complication of radiotherapy and one of the major causes of death in sub-acute phase after accidental exposure to high dose radiation. C57BL/6 mice were exposed to 1 Gy γ-ray radiation daily for 5 days in succession (a total of 5 Gy), and given nicaraven or a placebo after each exposure. The mice were sacrificed 2 days after the last radiation treatment, and the protective effects and relevant mechanisms of nicaraven in hematopoietic stem/progenitor cells with radiation-induced damage were investigated by ex vivo examination. We found that post-radiation administration of nicaraven significantly increased the number, improved the colony-forming capacity, and decreased the DNA damage of hematopoietic stem/progenitor cells. The urinary levels of 8-oxo-2′-deoxyguanosine, a marker of DNA oxidation, were significantly lower in mice that were given nicaraven compared with those that received a placebo treatment, although the levels of intracellular and mitochondrial reactive oxygen species in the bone marrow cells did not differ significantly between the two groups. Interestingly, compared with the placebo treatment, the administration of nicaraven significantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α in the plasma of mice. Our data suggest that nicaraven effectively diminished the effects of radiation-induced injury in hematopoietic stem/progenitor cells, which is likely associated with the anti-oxidative and anti-inflammatory properties of this compound.

The potential benefits of nicaraven to protect against radiation-induced injury in hematopoietic stem/progenitor cells with relative low dose exposures

“…On the mechanism, agreed well with the result of recent study in mice received high dose radiation [14], surprisingly, the ROS level was only slightly decreased in these purified c-kit + stem/progenitor cells from mice received nicaraven when compared to those received placebo treatment. This again suggests that nicaraven protection against radiation injury seems to be associated with other mechanism rather than as simple as a radical scavenger.…”

“…To explore the effect and relevant mechanisms of nicaraven for protecting radiation-induced injury in hematopoietic stem/progenitor cells, mice were daily exposed to 50 mGy γ-rays for 30 days in sequences (cumulative dose of 1.5 Gy). Intraperitoneal injection with 100 mg/kg nicaraven [14] (Nicaraven group, n=6) or saline only (Placebo group, n=6) was done within 30 minutes before each exposure. Mice were victimized 24 hours after the last exposure, and samples of blood and bone marrow cells were collected for the subsequent experiments.…”

“…We have recently demonstrated that the administration of nicaraven to mice soon after the exposure to a high dose of γ-ray attenuates the radiationinduced injury of hematopoietic stem/progenitor cells, via reduction of DNA damage of cells and inhibition of inflammation [14]. Taking the safety profile of nicaraven and the potential long-term healthy risk of occupational radiation exposures in consideration [2,15], it will be so interesting to confirm the prophylactic effect of nicaraven on radiationinduced injury, especially on these immature stem/progenitor cells after the exposure to relatively lower dose.…”

Nicaraven Attenuates Postoperative Systemic Inflammatory Responses-Induced Tumor Metastasis

“…The timing and dosage of nicaraven administration were based on our past studies, but it was required to be further validated by additional experiments. 3,10,15 Increasing evidences have shown the relationship between inflammatory cytokines/cells and tumor metastasis in recent years. It has been reported that TNF-a enhances tumor invasiveness and alters the tumor microenvironment to promote metastasis.…”

NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation

“…Inhibition of HSPC self-renewal or myelosuppression induced by IR is a direct consequence of DNA damage, leading to apoptosis, senescence, or cell cycle arrest (2,12,13). Antioxidants, antiapoptotic cytokines, or hematopoietic growth factors that could improve HSPC survival, maintenance, and/ or proliferation are being evaluated as radiomitigators (14)(15)(16).…”