Figure 1.

Release of acid sphingomyelinase (ASM) in the course of stress response and mode of action of its inhibition. Exposition of a cell membrane to external harmful stress events such as endogenous or exogenous stimuli (bacterial endotoxin, pro-inflammatory cytokines, pore-forming toxins, Table 2) is followed by intracellular Ca⁺⁺ influx, triggering the exocytosis of lysosomes, where ASM was bound to the inner lysosomal membrane by SAP domain. In the extracellular space, ASM mediates hydrolysis of SM (abundantly embedded into the outer leaflet of the membrane), generates ceramide, facilitating remodeling, and repair of the membrane (restoring integrity), as well as pathogen entry. As a hallmark of ceramide-induced signal transduction, due to the trend for self-aggregation and formation of ceramide-enriched microdomains, subunits of receptor proteins are reorganized to functionally active receptor complexes such as TLR4, TNFR, etc. As a result, an increase in signaling quality and intensity is observed, controlling an adequate cellular response to external harmful stimuli. On the right panel, the mode of action of cationic amphiphilic substances is illustrated: in an uncharged form at physiological pH value, the compounds diffuse across the cellular membrane through the cytoplasma into the lysosome, where the weak basic nitrogen atom of the compound is protonated because of the acid pH value of the lysosome. The protonated compound interacts with the sapsonin domain of ASM, detaching them from the membrane, then undergoing proteolytic inactivation. Following stimulation and release, the inactivated ASM is unable to contribute to ceramide generation at the outer leaflet of the membrane. Due to similar physicochemical properties, a long list of cationic amphiphilic substances with a broad range of clinical indications, but most of them used in daily care as antidepressive drugs, are found to function as functional inhibitors of acid sphingomyelinase (FIASMA) and to effectively control stress-induced ceramide generation. Most of the available FIASMAs are licensed for medical use in humans, are minimally toxic, and may therefore be applied for disease states associated with increased activity of ASM.