Reactive Carbonyl Species Scavengers—Novel Therapeutic Approaches for Chronic Diseases

Abstract

Purpose of the review To summarize recent evidence supporting the use of reactive carbonyl species scavengers in the prevention and treatment of disease. Recent findings The newly developed 2-aminomethylphenol class of scavengers shows great promise in preclinical trials for a number of diverse conditions including neurodegenerative diseases and cardiovascular disease. In addition, new studies with the thiol-based and imidazole-based scavengers have found new applications outside of adjunctive therapy for chemotherapeutics. Summary Reactive oxygen species (ROS) generated by cells and tissues act as signaling molecules and as cytotoxic agents to defend against pathogens, but ROS also cause collateral damage to vital cellular components. The polyunsaturated fatty acyl chains of phospholipids in the cell membranes are particularly vulnerable to damaging peroxidation by ROS. Evidence suggests that the breakdown of these peroxidized lipids to reactive carbonyls species plays a critical role in many chronic diseases. Antioxidants that abrogate ROS-induced formation of reactive carbonyl species also abrogate normal ROS signaling and thus exert both beneficial and adverse functional effects. The use of scavengers of reactive dicarbonyl species represent an alternative therapeutic strategy to potentially mitigate the adverse effects of ROS without abrogating normal signaling by ROS. In this review, we focus on three classes of reactive carbonyl species scavengers: thiol-based scavengers (2-mercaptoethanesulfonate and amifostine), imidazole-based scavengers (carnosine and its analogs), and 2-aminomethylphenols-based scavengers (pyridoxamine, 2-hydroxybenzylamine, and 5’-O-pentyl-pyridoxamine) that are either undergoing pre-clinical studies, advancing to clinical trials, or are already in clinical use.

Scavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr−/− mice

“…Although a few trials of dietary antioxidants in humans demonstrated reductions in atherosclerosis and cardiovascular events, the majority of large clinical outcomes trials with antioxidants have failed to show any benefit in terms of reduced cardiovascular events. Possible reasons for the failure of these trials to reduce cardiovascular events, include inadequate doses of antioxidants being used in the trials 1, 16 and the inhibition of normal ROS signaling that may be anti-atherogenic 26 . Treatment with scavengers of reactive dicarbonyl species derived from lipid peroxidation represents a novel alternative therapeutic strategy that will inhibit the adverse effects of ROS without destroying normal signaling mediated by ROS 26 .…”

“…Possible reasons for the failure of these trials to reduce cardiovascular events, include inadequate doses of antioxidants being used in the trials 1, 16 and the inhibition of normal ROS signaling that may be anti-atherogenic 26 . Treatment with scavengers of reactive dicarbonyl species derived from lipid peroxidation represents a novel alternative therapeutic strategy that will inhibit the adverse effects of ROS without destroying normal signaling mediated by ROS 26 . In the current study, we sought to examine the potential of a reactive lipid dicarbonyl scavenger, to prevent the development of atherosclerosis in Ldlr -/mice.…”

Carbonyl scavengers as pharmacotherapies in degenerative disease: Hydralazine repurposing and challenges in clinical translation

“…An ideal LDE-scavenger will possess a combination of at least three core characteristics, namely ready reactivity with noxious LDEs; drug-like physicochemical properties that confer good tissuepenetrating capabilities; and a limited pharmacological profile due to minimal activity at "offtarget" receptors [20]. The possession of a nucleophilic group that confers reactivity with LDEs is especially important, and typical cytoprotective scavengers possess one or more nucleophilic heteroatoms such as an O, N, or S [18].…”

“…One alternative to antioxidant suppression of LDE production involves using carbonyl-trapping molecules to directly intercept reactive LDEs within cells and tissues [16][17][18][19]. Since LDEs are less likely to play the essential cell signalling functions attributed to reactive oxygen species, this strategy seems less susceptible to the side-effects that hamper clinical translation of radicalquenching antioxidants.…”

A New Participant in the Pathogenesis of Alcoholic Gastritis: Pyroptosis

“…1A). [38] and induced oxidative stress and inflammation in the gastric tissues [39]. As part of the inflammation progress, pyroptosis is involved in many chronic diseases [40][41][42][43].…”