A multiple sclerosis drug sheds light on astrocyte biology

Pathological astroglial secretion may contribute to a number of neuronal diseases including amyotrophic lateral sclerosis and multiple sclerosis (Barres 2008, Verkhratsky et al. 2013). In this issue of Acta Physiologica, the paper entitled ‘Alterations of calcium homeostasis in cultured rat astrocytes evoked by bioactive sphingolipids’ by Stenovec et al. (2014) reports that sphingosine, an intracellular metabolite, and a sphingosine-mimetic drug approved for treatment of multiple sclerosis inhibit astroglial secretion by increasing intracellular calcium concentration. The authors identify several steps of intracellular signalling pathway responsible for down-regulation of secretion, including disruption of microtubule-driven vesicular traffic. Multiple sclerosis is a chronic inflammatory neurodegenerative disease that leads to demyelination of nerve cells in the brain and spinal cord by infiltrating lymphocytes (Brinkmann et al. 2010). Normally, a person’s nervous system would be inaccessible to the white blood cells due to the blood–brain barrier. However, in multiple sclerosis, the blood–brain barrier breaks down in a section of the brain or spinal cord for unknown reasons, allowing white blood cells called T lymphocytes to cross it and attack the myelin (Brinkmann et al. 2010). Upon injury to nerve cells, astrocytes fill up the space to form a glial scar, repairing the area and replacing neurons that cannot regenerate (Barres 2008, Verkhratsky et al. 2013). Astrocytes, the most abundant cells of the human brain, provide metabolic support to neurons and actively tune synaptic activity of neurons. Astrocytes are also involved in the microcirculation of the brain by forming intimate connections with vascular cells (Abbott et al. 2006). Insults to neurons in the central nervous system caused by infection, trauma, autoimmune responses and neurodegenerative diseases cause reactive astrocytes, which initiate the process of astrogliosis (Barres 2008, Verkhratsky et al. 2013). Proliferating reactive astrocytes reduce the spread of inflammatory cells, repair the blood–brain barrier, decrease tissue damage and lesion size and decrease neuronal loss and demyelination. Disturbance of functions normally performed by astrocytes has the potential to underlie neural dysfunction and pathology in various conditions including multiple sclerosis. A key process mediating astrocyte communication with neighbouring cells is regulated exocytosis (Potokar et al. 2013). This multistage, spatially and temporally highly organized process consists of many steps leading to merger between secretory organelles and the plasma membrane. Astrocytes release glutamate, serine, ATP, tumour necrosis factor-a, interleukins and prostaglandins, which play a crucial role in the progression of inflammatory diseases of the nervous system (Potokar et al. 2013, Verkhratsky et al. 2013). Previous work by Robert Zorec and colleagues demonstrated that in astrocytes, cell-permeable sphingosine affects regulated exocytosis by inhibiting vesicle mobility and preventing vesicle interaction with the plasma membrane docking/release sites (Trkov et al. 2012). The cell-permeable sphingosine-like molecules, briefly applied at 10 lM concentration, down-regulated the mobility of peptidergic, glutamatergic and LysoTracker-positive vesicles and potently inhibited the release of peptides and glutamate from stimulated astrocytes (Trkov et al. 2012). In this study (Stenovec et al. 2014), Zorec and colleagues addressed the specific intracellular pathways that lead to sphingosinedriven inhibition of astrocytic secretion, demonstrating that a new multiple sclerosis drug FTY720 is a faithful mimetic of sphingosine. The past decade has seen an explosive advancement in the field of sphingolipid signalling. Most of the regulatory proteins and enzymes involved in sphingolipid metabolism and relevant receptors have been cloned. In addition, specific agonists and antagonists of receptors and inhibitors of signalling enzymes were developed (Maceyka & Spiegel 2014). Inside the cell, sphingosine – the key constituent of sphingolipids – is either synthesized de novo or generated from sphingomyelin by the dual action of sphingomyelinase and ceramidase. Sphingosine is then converted into sphingosine-1-phosphate by cytosolic or nuclear kinases. FTY720, also known as fingolimod, is a sphingosine mimetic introduced by Novartis as the first-in-class orally bioavailable drug (Gilenya) for the treatment of multiple sclerosis (Brinkmann et al. 2010). FTY720 is phosphorylated in vivo to FTY720 phosphate by SphK2 to a mimetic of sphingosine-1-phosphate. According to the marketing authorization holder, it acts via the phosphorylated form of FTY720 (FTY720P) to target the immune system by interacting with S1P receptors on lymphocytes. FTY720-P acts as a functional receptor antagonist, causing internalization and degradation of S1P receptors (Maceyka &