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Intestinal Epithelial Regeneration in Response to Ionizing Irradiation
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Necrostatin-1 rescues mice from lethal irradiation.
Zhentai Huang1, Michael Epperly2, Simon C Watkins3
1Center for Free Radical and Antioxidant Health, Department of Environmental and Occupational Health, University of Pittsburgh, United States.
Biochimica Et Biophysica Acta
|January 24, 2016
Summary
Necrostatin-1 shows radiomitigative potential by inhibiting necroptosis, a form of programmed necrosis, after total body irradiation (TBI). This suggests RIPK1 inhibitors may be promising for mitigating radiation injury.
Area of Science:
- Radiation biology
- Cell death pathways
- Medical countermeasures
Background:
- Emerging need for medical products to treat radiation exposure consequences.
- Ionizing radiation causes cell death via apoptosis and later, necrosis.
- Necroptosis, a programmed necrosis, may contribute to radiation disease.
Purpose of the Study:
- Evaluate the radiomitigative potential of necrostatin-1.
- Investigate the role of necroptosis in radiation-induced cell death.
- Assess necrostatin-1's efficacy after total body irradiation (TBI).
Main Methods:
- Administered necrostatin-1 intravenously 48 hours after 9.5Gy TBI in mice.
- Assessed receptor interacting protein kinase 3 (RIPK3) serine phosphorylation in ileum.
- Utilized apoptosis-resistant cytochrome c(-/-) cells to study radiation-induced necroptosis.
- Employed RNAi knockdown of RIPK1 and RIPK3.
Main Results:
- Necrostatin-1 treatment attenuated radiation-induced RIPK3 serine phosphorylation.
- Necrostatin-1 administration improved survival rates compared to vehicle control.
- Radiation induced necroptosis in apoptosis-resistant cells, inhibited by necrostatin-1 and RIPK1/RIPK3 knockdown.
- 1-methyl-L-tryptophan did not show radiomitigative effects.
Conclusions:
- Necroptosis plays a significant role in radiation-induced cell death and mortality.
- Necrostatin-1's beneficial effects are likely due to RIPK1-mediated necroptosis inhibition.
- Necrostatin-1 and other RIPK1 inhibitors are promising therapeutic agents for radiomitigation.
