title: Quinic acid derivative KZ-41 exhibits radiomitigating activity in preclinical models of radiation injury.
abstract: Acute 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-LD₈₀/₃₀, ¹³⁷Cs; ∼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 (¹³⁷Cs; 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.
authors.affiliation: Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, Tennessee, 38163.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Thompson
authors.forename: Kui
authors.initials: K
authors.lastname: Zeng
authors.forename: Christy M
authors.initials: CM
authors.lastname: Wilson
authors.forename: Mostafa W
authors.initials: MW
authors.lastname: Gaber
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
authors.forename: Charles R
authors.initials: CR
authors.lastname: Yates
mesh_terms: D000818:Animals; D001773:Blood Cells / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D011801:Quinic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000473:pathology; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D057772:Vascular System Injuries / Q000188:drug therapy / Q000473:pathology*; D014699:Venules / Q000187:drug effects* / Q000293:injuries*
chemical_list: C569814:KZ 41 compound; D011837:Radiation-Protective Agents; D014409:Tumor Necrosis Factor-alpha; D011801:Quinic Acid
keywords: radiation combined injury; radiomitigant; total body irradiation; vascular injury; wound healing