Radioprotective Activity of the Nitric Oxide Synthase Inhibitor T1023. Toxicological and Biochemical Properties, Cardiovascular and Radioprotective Effects
Abstract
This study explored the toxicological, biochemical, vasotropic, and radiomodifying properties of a novel nitric oxide synthase (NOS) inhibitor, compound T1023. Toxicity was evaluated through acute toxicity testing in mice via intraperitoneal (i.p.) administration. The NOS-inhibitory properties of T1023 were examined using radiometric analysis and electron paramagnetic resonance spectroscopy, both in vitro and in vivo. Vasoactive effects were assessed through analysis of central hemodynamics in rats.
Radiobiological effects were studied using endogenous and exogenous spleen colony assays and 30-day survival tests. Additionally, morphological changes in peripheral blood and bone marrow were analyzed in mice undergoing hematopoietic acute radiation syndrome (H-ARS) after treatment with T1023.
T1023 demonstrated a favorable safety profile, with an LD₁₀ of 317 mg/kg and an LD₅₀ of 410 mg/kg. It acts as a competitive NOS inhibitor with notable selectivity—being 10 to 15 times more selective for endothelial (eNOS) and inducible NOS (iNOS) over neuronal NOS (nNOS), with IC₅₀ values of 52.3 µM (nNOS), 3.2 µM (iNOS), and 5.1 µM (eNOS). In vivo, T1023 inhibited NOS activity and increased vascular tone. A single i.p. dose exceeding 1/8 of the LD₁₀ significantly reduced cardiac output by 40–50% for over 90 minutes, inducing transient hypoxia.
As a hypoxic radioprotector, T1023 exhibited radioprotective effects only when administered prophylactically—between 5 to 120 minutes before total-body irradiation (TBI)—and only at doses that caused circulatory suppression (≥1/8 LD₁₀ or 40 mg/kg in mice). This protective effect aligned with the timeline of reduced cardiac output. No radioprotective activity was observed when the compound was administered in vitro or within the first four hours after TBI. Optimal radioprotective doses (1/5 to 1/4 LD₁₀) were found to be relatively safe.
Moreover, T1023 effectively prevented both H-ARS and gastrointestinal acute radiation syndrome (G-ARS) in vivo, with a dose modifying factor (DMF) ranging from 1.6 to 1.9. In a mouse model of H-ARS, a single prophylactic i.p. injection of 75 mg/kg produced significant clinical benefits: early bone marrow damage indicators were reduced by 40%, maximum neutropenia and thrombocytopenia were lowered by 2–2.5 times, and recovery time was shortened by 30–40%.
Overall, the experimental data and existing literature suggest that NOS inhibitors represent a distinct class of vasoactive radioprotectors that exert their effects through a specific hypoxic mechanism. These findings JH-RE-06 highlight their potential in developing effective and safe strategies for acute radiation syndrome (ARS) prevention.