Carbonyl-trapping therapeutic strategies

Under conditions of oxidative stress, aldehyde or ketone products are generated nonenzymatically by lipid peroxidation or form spontaneously from simple sugars. Many aldehydes, in particular, are cytotoxic. They may react with primary amine groups to form Schiff bases, which may subsequently rearrange into more chemically stable structures. In biological systems, such reactions may disrupt normal oligonucleotide structure, may interfere with the biological activity of numerous structural or enzymatic polypeptides, and may covalently cross-link proteins and lipids (eg, phosphatidylethanolamine). Once thought to be largely epiphenomenal, such events are now known to be central to the etiologies of a spectrum of neurodegenerative diseases, chronic inflammatory diseases, and pathophysiologically related disorders. Opportunities exist for therapeutic intervention in these disease states by use of certain water-soluble, small-molecular-weight drugs that contain primary amine groups. Such pharmaceutical agents, administered orally, can form Schiff-base derivatives with toxic carbonyl substances and thus protect cellular components. Future studies of such carbonyl-trapping agents may include their use in combination with other classes of drugs, such as antioxidants, anti-inflammatory products, or neuroactive agents. This conceptually simple approach may offer new opportunities for improved clinical management of many chronic disease states.