We therefore hypothesizethat FIASMAs also penetrate the BBB andare therefore overrepresented in drugs active in the central nervous system. This is supported by the fact that FIASMAs represent different therapeutic classes and different structural classes as evidenced by their ATC-codes. Our results prove that functional inhibition of ASM does not depend on a specific molecular drug class. Instead of specific structural prerequisites, functional inhibition of ASM requires specific physicochemical characteristics of compounds, resulting in high intra-lysosomal concentrations and partitioning of the drug into the inner leaf of the lysosomal membrane. Ceramide and its metabolite sphingosine-1-phosphate have been shown to antagonistically regulate apoptosis, cellular differentiation, proliferation and cell migration. Inhibition of ASM results in anti-apoptotic, proliferative and anti-inflammatory effects. ALK5 Inhibitor II Furthermore, ASM could play a key role in the pathophysiology of depression and in the RAD001 action of antidepressant drugs. Inhibitors of ASM therefore hold promise for a number of new clinical therapies. Several examples are given here: Induction of stroke by experimental ischemia of the brain was shown to correlate with an activation of the ASM and a release of ceramide. Importantly, ASM-deficient mice were protected from tissue damage caused by focal cerebral ischemia. Furthermore, the ethanol-induced neuronal cell death is mediated, at least in part, by activation of ASM and generation of ceramide. In addition, the lethal gastrointestinal syndrome, which limits the efficacy of radiation and chemotherapy, apparently results from apoptotic damage of the endothelial cells of the microvasculature of the small intestine. Genetic inactivation of ASM prevents this toxicity. Infection induced by the human immunodeficiency virus type Iserves as a further example. HIV-1 induces a dramatic depletion of CD4+ T cells in infected individuals, finally leading to AIDS. The massive loss of CD4 T-lymphocytes is assumed to result from apoptosis, probably due to enhanced sphingomyelin breakdown and accumulation of intracellular ceramide. Interestingly, HIV-1 infected long-term nonprogressors have less elevated lymphocyte-associated ceramide than subjects with evolving AIDS, which is paralleled by a lower frequency of apoptotic CD4 and CD8 cells in long-term nonprogressors compared to patients with AIDS. The endotoxic shock syndrome, which is characterized by systemic inflammation, multiple organ damage, circulatory collapse and death, is caused by disseminated endothelial apoptosis sequentially mediated by TNF and ceramide generation. Blocking of this cascade by ASM inhibitors should be preventive and/or therapeutic against the endotoxic shock syndrome. Finally, an imbalance between ASM and acid ceramidase followed by ceramide accumulation has been demonstrated in the hereditary disease cystic fibrosis. In experimental animals, FIASMAs normalize pulmonary ceramide and inflammation. In a clinical pilot study, amitriptyline 6 led to an improved respiratory function in affected patients. Further examples include the treatment of e.g. Alzheimer’s disease, major depression, inflammatory bowel disease, liver cell death and anaemia occurring in Wilson disease, and pulmonary edema in acute lung injury. Recently, it has been shown that gilenya, a drug licensed for treatment of multiple sclerosis, acts as a FIASMA. This novel mechanism of action may explain at least in part the beneficial effects of gilenya in multiple sclerosis. AC is a lysosomal enzyme degrading ceramide to sphingosine.