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Improved Total-Body Irradiation Survival by Delivery of Two Radiation Mitigators that Target Distinct Cell Death Pathways
- Source :
- Radiation Research. 189:68
- Publication Year :
- 2017
- Publisher :
- Radiation Research Society, 2017.
-
Abstract
- The acute lethality of total-body irradiation (TBI) involves damage to multiple organs, including bone marrow and intestine. Ionizing radiation mitigators that are effective when delivered 24 h or later after TBI include the anti-apoptotic drug, JP4-039 and the anti-necroptotic drug, necrostatin-1. In contrast to effective delivery of JP4-039 at 24 h after TBI, necrostatin-1 is most effective when delivery is delayed until 48 h, a time that correlates with the elevation of necroptosis-inducing inflammatory cytokines and necroptosis-induced serine phosphorylation of receptor-interacting serine/threonine-protein kinase-3 (RIP3) in tissues. The goal of this work was to determine whether administration of JP4-039 influenced the optimal delivery time for necrostatin-1. We measured daily levels of 33 proteins in plasma compared to intestine and bone marrow of C57BL/6NTac female mice over a 7-day time period after 9.25 Gy TBI (LD50/30). Protein responses to TBI in plasma were different from those measured in intestine or bone marrow. In mice that were given JP4-039 at 24 h after TBI, we delayed necrostatin-1 delivery for 72 h after TBI based on measured delay in RIP-3 kinase elevation in marrow and intestine. Sequential delivery of these two radiation mitigator drugs significantly increased survival compared to single drug administration.
- Subjects :
- 0301 basic medicine
Drug
Pathology
medicine.medical_specialty
Programmed cell death
Indoles
Time Factors
Cell Survival
media_common.quotation_subject
Biophysics
Apoptosis
Pharmacology
Article
Ionizing radiation
Proinflammatory cytokine
Mice
03 medical and health sciences
0302 clinical medicine
Bone Marrow
medicine
Animals
Radiology, Nuclear Medicine and imaging
Intestinal Mucosa
Phosphorylation
media_common
Radiation
Cell Death
Kinase
business.industry
Imidazoles
Blood Proteins
Total body irradiation
Intestines
Mice, Inbred C57BL
030104 developmental biology
medicine.anatomical_structure
Receptor-Interacting Protein Serine-Threonine Kinases
030220 oncology & carcinogenesis
Female
Nitrogen Oxides
Bone marrow
business
Whole-Body Irradiation
Subjects
Details
- ISSN :
- 00337587
- Volume :
- 189
- Database :
- OpenAIRE
- Journal :
- Radiation Research
- Accession number :
- edsair.doi.dedup.....5b64969c17f420db874cb94229f7ebed