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Quinic Acid Derivative KZ ‐41 Exhibits Radiomitigating Activity in Preclinical Models of Radiation Injury
Author(s) -
Thompson Karin E.,
Zeng Kui,
Wilson Christy M.,
Gaber Mostafa W.,
Miller Duane D.,
Yates Charles R.
Publication year - 2014
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21164
Subject(s) - saline , medicine , blood flow , total body irradiation , nuclear medicine , chemistry , anesthesia , pharmacology , surgery , chemotherapy , cyclophosphamide
Preclinical ResearchAcute radiation syndrome is induced when a significant portion of the body receives high‐dose, as well as high‐dose rate, radiation. We have previously identified a quinic acid‐based derivative, KZ ‐41, that protects from radiation injury. Further preclinical efficacy studies were conducted to determine the radiomitigating activity of KZ ‐41. C57BL /6 mice received total body irradiation ( TBI — LD 80/30 , 137 Cs ; ∼2 min) followed by either normal saline or KZ ‐41 (100 mg/kg sc ∼26 h post‐ TBI ). KZ ‐41 increased 30‐day survival by approximately 45% compared with vehicle controls ( P < 0.05). To further investigate the potential radiomodulating mechanisms of KZ ‐41, we developed a combined radiation and vascular injury model. C57BL /6 mice surgically fixed with dorsal windows for dermal vasculature imaging received either sham or TBI ( 137 Cs ; 6 Gray). Postcapillary venule injury was induced (24, 48, 72, and 96 h post‐ TBI ) followed by imaging at 5 min and 24 h to assess clot formation and blood flow. Impairment in flow ( P < 0.05) and clot formation ( P < 0.05) were observed as early as 48 and 72 h, respectively. Thus, vascular injury 72 h post‐TBI was used to evaluate intervention ( KZ ‐41; 100 mg/kg i.p. at 12, 36, and 60 h post‐ TBI ) on radiation‐induced changes in both flow and clot formation. KZ ‐41, although not improving flow, increased clot formation ( P < 0.05). Platelet counts were lower in both irradiated groups compared with sham controls ( P < 0.05). In summary, KZ ‐41 exerts radiomitigating activity in lethally irradiated mice. Imaging results suggest KZ ‐41 exerts radiomitigating activity through mechanisms involving promotion of initial clot formation and vascular flow restoration. The imaging model described herein is useful for further examination of radiation‐induced vascular injury repair mechanisms.