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.

Quinic acid derivatives inhibit dengue virus replication in vitro

“…Recently, it has been demonstrated that the amides of quinic acid derivatives exhibited anti-inflammatory activities both in vitro and in vivo and therefore they may serve as attractive options for therapeutic use [ 24 , 25 ]. Furthermore, one of these amides was found to enhance the survival of C57/Bl6 mice that were exposed to lethal radiation by 45 % [ 26 ]. Additionally, a quinic acid ester (QAE) prolonged cell survival by reducing replication in S-phase cells, indicating that it protects cells from damage by allowing time for cellular DNA damage repair to occur [ 27 ].…”

Discoveries of Targets and Novel Agents for the Treatment of Ischemic Retinopathy and Neovascular Disease

“…In this chapter, we have demonstrated that absorbed doses of radiation to the human REC provoked an inflammatory response characterized by rapid induction in p38 stress kinase-mediated pathways and downstream effectors, e.g., tumor suppressor, p53 and ICAM-1. We have previously demonstrated that the quinic acid derivative KZ-41 modulates cellular responses to genotoxic stress via mechanisms involving disruption of p38 signal transduction [88,90,183]. We extended these findings by demonstrating that KZ-41 also modulates p38 activity in the irradiated REC.…”

“…Previously identified radiomitigant, KZ-41 provided a ~50% survival benefit following total body irradiation (TBI; LD80/30) and enhanced vascular repair mechanisms in a murine combined radiation and vascular injury model [88,89]. In an in vitro model of genotoxic stress using the alkylating agent melphalan, we also showed KZ-41 to specifically counteract p38-dependent pro-apoptotic and inflammatory signaling in primary human RECs [90].…”

“…Inflammation of and damage to microvessels leads to inflammatory and reparative cell homing and adhesion, which is touted as the primary mechanism of early ischemic injury in both diabetic retinopathy (DR) and radiation retinopathy (RR). Previous work identified KZ-41 as a radiomitigant/protectant by providing a significant survival benefit in the murine TBI model, as well as restoring microvascular flow in combined radiation and vascular injury paradigms [88,89]. In an in vitro model of genotoxic stress using the alkylating agent melphalan, we showed KZ-41 specifically counteracts p38 MAPKdependent pro-apoptotic and inflammatory signaling in primary human retinal endothelial cells (REC) [90].…”

“…Quinic acid derivatives have been suggested to inhibit the activity of NFkB and are potentially useful as anti-inflammatory agents, specifically in providing protective benefits following radiation injury [121]. We further explore this genetic link in more detail in Chapter 4 with KZ-41, a quinic acid derivative known to provide a substantial survival benefit in TBI models [88].…”