Potentialities and pitfalls accompanying chemico-pharmacological strategies against endogenous electrophiles and carbonyl stress.

The use of powerful analytical technologies to detect endogenous carbonyls formed as byproducts of oxidative cell injury has revealed that these species contribute to many human diseases. As electrophiles, they are attacked by reactive centers in cell macromolecules to form adducts, the levels of which serve as useful biomarkers of oxidative cell injury. Because the pathobiological significance of such damage is often unclear, the possibility of using low molecular weight drugs as exploratory sacrificial nucleophiles to intercept reactive carbonyls within cells and tissues is appealing. This perspective highlights the potential benefits of using carbonyl scavengers to evaluate the significance of endogenous carbonyls in particular diseases but also canvasses a number of challenges confronting this therapeutic strategy. Chief among the latter is the task of confirming that carbonyl sequestration underlies any suppression of disease symptoms elicited by these multipotent reagents, an issue needing clarification if these compounds are to command consideration as drug interventions in humans. Other problems include adverse consequences of reactions between carbonyl scavengers and important endogenous carbonyls (e.g., neurotoxicity due to pyridoxal depletion), as well as the potential for drugs to form ternary complexes with carbonylated cell proteins, raising the prospect of immunotoxicological outcomes. Strategies for moving carbonyl sequestering reagents from the laboratory bench to a clinical testing environment are discussed within the context of the search for new treatments for spinal cord injury, one of the most debilitating medical conditions sustainable by humans. This condition seems an appropriate test case for assessing carbonyl sequestering drugs given growing evidence for noxious carbonyls in the wave of neuronal cell death that follows traumatic injury to the spinal cord.