Neutral sphingomyelinase as a target for drug design

The sphingolipid ceramide is an important second messenger assumed to be involved in fundamental processes, including proliferation, differentiation and growth arrest, as well as the induction of apoptosis. Ceramide is generated in a ubiquitous and evolutionarily conserved signaling pathway called the sphingomyelin pathway, through the action of distinct isoforms of sphingomyelinases. An improved understanding of sphingomyelinase-dependent signaling may offer significant insights into the regulation of physiological and pathological processes and may finally provide novel strategies and new targets for pharmacological intervention (e.g., in inflammatory responses, neurodegenerative diseases and cancer). This article summarizes the current knowledge of the role of neutral sphingomyelinase (N-SMase) in cell signaling pathways, and its potential meaning, and demonstrates the opportunity of a specific inhibition of N-SMases as a novel therapeutic target.