Abstract
The central nervous system is characterized by a high content of sphingolipids and by a high diversity in terms of different structures. Stage- and cell-specific sphingolipid metabolism and expression are crucial for brain development and maintenance toward adult age. On the other hand, deep dysregulation of sphingolipid metabolism, leading to altered sphingolipid pattern, is associated with the majority of neurological and neurodegenerative diseases, even those totally lacking a common etiological background. Thus, sphingolipid metabolism has always been regarded as a promising pharmacological target for the treatment of brain disorders. However, any therapeutic hypothesis applied to complex amphipathic sphingolipids, components of cellular membranes, has so far failed probably because of the high regional complexity and specificity of the different biological roles of these structures. Simpler sphingosine-based lipids, including ceramide and sphingosine 1-phosphate, are important regulators of brain homeostasis, and, thanks to the relative simplicity of their metabolic network, they seem a feasible druggable target for the treatment of brain diseases. The enzymes involved in the control of the levels of bioactive sphingoids, as well as the receptors engaged by these molecules, have increasingly allured pharmacologists and clinicians, and eventually fingolimod, a functional antagonist of sphingosine 1-phosphate receptors with immunomodulatory properties, was approved for the therapy of relapsing–remitting multiple sclerosis. Considering the importance of neuroinflammation in many other brain diseases, we would expect an extension of the use of such analogs for the treatment of other ailments in the future. Nevertheless, many aspects other than neuroinflammation are regulated by bioactive sphingoids in healthy brain and dysregulated in brain disease. In this review, we are addressing the multifaceted possibility to address the metabolism and biology of bioactive sphingosine 1-phosphate as novel targets for the development of therapeutic paradigms and the discovery of new drugs.
Highlights
Sphingolipids are a wide group of eukaryotic cellular lipids, whose common structural feature is the presence of a 2-amino1,3-dihydroxy-octadec-4-ene, trivially known as “sphingosine” (Roisen et al, 1981) (2S,3R,4E)
Ceramide is the precursor for the biosynthesis of amphipathic sphingolipids, characterized by the presence of a polar head group of different nature and chemical complexity linked to the hydroxyl group at the position 1 of ceramide
We recently showed that rHIgM22 stimulated the proliferation of astrocytes in mixed glial cells because of the increased production and release of sphingosine 1-phosphate (S1P), suggesting that S1P signaling might be significant in the interplay of different cell types involved in the complex series of events eventually leading to myelin repair (Grassi et al, 2019)
Summary
Sphingolipids are a wide group of eukaryotic cellular lipids, whose common structural feature is the presence of a 2-amino1,3-dihydroxy-octadec-4-ene, trivially known as “sphingosine” (Roisen et al, 1981) (2S,3R,4E). Sphingolipids are ubiquitous components of mammalian cell membranes; their distribution is highly organ- and tissue-specific. S1P derived from the catabolism of ceramide and more complex sphingolipids is an important biologically active mediator involved in diverse signal transduction pathways that regulate many different cell functions, in some cases, with effects opposed to those of ceramide. It has been shown that S1P is able to mediate calcium signaling in cultured cerebellar astrocytes, whereas it failed to trigger any calcium-mediated response in differentiated cerebellar neurons This effect could be important for neuron–glia communication in the cerebellum (Giussani et al, 2007). It has been demonstrated that S1P induced i) apoptosis in hippocampal neurons (Moore et al, 1999) as well as ii) accumulation of TABLE 1 | Research and clinical use of enzymes of S1P metabolism
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