Assessment of Gadobutrol Safety in Combination with Ionizing Radiation Using a Preclinical MRI-Guided Radiotherapy Model.

MR-linac technology enhances the precision of therapeutic radiation by clarifying the tumor-normal tissue interface and provides the potential for adaptive treatment planning. Accurate delineation of tumors on diagnostic magnetic resonance imaging (MRI) frequently requires gadolinium-based contrast agents (GBCAs). Despite generally being considered safe, previous literature suggests that GBCAs are capable of contrast-induced acute kidney injury (AKI). It is unclear if the risk for AKI is enhanced when GBCAs are administered concurrently with ionizing radiotherapy. During irradiation, gadolinium may be liberated from its chelator which may induce AKI. The goal of this work was to determine if radiation combined with GBCAs increased the incidence of AKI. Using a preclinical MRI-guided irradiation system, where MRI acquisitions and radiation delivery are performed in rapid succession, tumor-bearing mice with normal kidney function were injected with GBCA and treated with 2, 8 or 18 Gy irradiation. Renal function was assessed on days three and seven postirradiation to assess for AKI. No clinically relevant changes in blood urea nitrogen and creatinine were observed in any combination of GBCA and radiation dose. From these data, we conclude that GBCA in combination with radiation does not increase the risk for AKI in mice. Additional investigation of multiple doses of GBCA administered concurrently with irradiation is warranted to evaluate the risk of chronic kidney injury.

Biochemical characterization of the catecholaldehyde reactivity of L-carnosine and its therapeutic potential in human myocardium.

Oxidative deamination of norepinephrine (NE) and dopamine (DA) by monoamine oxidase (MAO) generates the catecholaldehydes 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL) and 3,4-dihydroxyphenylacetaldehyde (DOPAL), respectively, and H2O2. Catecholaldehydes are highly reactive electrophiles that have been implicated as causal factors in the etiology of neurodegenerative diseases and cardiac injury from ischemia and diabetes. The reactivity of both catechol and aldehyde groups enables the catecholaldehdyes to cross-link proteins and other biological molecules. Carnosine is a ß-alanyl-histidine dipeptide found in millimolar concentrations in brain and myocardium. It is well known to detoxify aldehydes formed from oxidized lipids and sugars, yet the reactivity of carnosine with catecholaldehydes has never been reported. Here, we investigated the ability of carnosine to form conjugates with DOPAL and DOPEGAL. Both catecholaldehydes were highly reactive towards L-cysteine (L-Cys), as well as carnosine; however, glutathione (GSH) showed essentially no reactivity towards DOPAL. In contrast, GSH readily reacted with the lipid peroxidation product 4-hydroxy-2-nonenal (4HNE), while carnosine showed low reactivity to 4HNE by comparison. To determine whether carnosine mitigates catecholaldehyde toxicity, samples of atrial myocardium were collected from patients undergoing elective cardiac surgery. Using permeabilized myofibers prepared from this tissue, mitochondrial respiration analysis revealed a concentration-dependent decrease in ADP-stimulated respiration with DOPAL. Pre-incubation with carnosine, but not GSH or L-Cys, significantly reduced this effect (p < 0.05). Carnosine was also able to block formation of catecholaldehyde protein adducts in isolated human cardiac mitochondria treated with NE. These findings demonstrate the unique reactivity of carnosine towards catecholaldehydes and, therefore, suggest a novel and distinct biological role for histidine dipeptides in this detoxification reaction. The therapeutic potential of carnosine in diseases associated with catecholamine-related toxicity is worthy of further examination.