A new study on mice published in Nature Neuroscience finds that fingolimod (Novartis brand name Gilenya) a first-in-class sphingosine-1-phosphate-receptor modulator currently used in treating persons with severe relapsing remitting MS, may also have therapeutic value in treating Post Traumatic Stress Disorder (PTSD).
The Nature Neuroscience study is titled “Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory” (Nature Neuroscience (2014) doi:10.1038/nn.3728). Corresponding author is Dr. Sarah Spiegel, Professor and Chair at the Virginia Commonwealth University School of Medicine Department of Biochemistry and Molecular Biology in Richmond, with primary authors Nitai C Hait and Laura E Wise, and Jeremy C Allegood, Megan O’Brien, Dorit Avni, Thomas M Reeves, Pamela E Knapp, Junyan Lu, Cheng Luo, Michael F Miles, Sheldon Milstien, and Aron H Lichtman, variously of the Departments of Medicine, Pharmacology and Toxicology, Biochemistry and Molecular Biology, Anatomy and Neurobiology, and the Massey Cancer Center at the Virginia Commonwealth University School of Medicine in Richmond, Virginia, and the State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Details of the Study:
The coauthors note that they’ve found FTY720 (fingolimod) has beneficial effects in the CNS that are not yet well understood, independent of its effects on immune cell trafficking. In their study they show that FTY720 enters the nucleus, where it is phosphorylated by sphingosine kinase 2 (SphK2), and that nuclear FTY720-P binds and inhibits class I histone deacetylases (HDACs), enhancing specific histone acetylations. FTY720 is also phosphorylated in mice and accumulates in the brain, including the hippocampus, inhibits HDACs and enhances histone acetylation and gene expression programs associated with memory and learning, and rescues memory deficits independently of its immunosuppressive actions.
Research in the Spiegel/Milstien laboratory at Virginia Commonwealth University is focused on the enigmatic lipid mediator, sphingosine-1-phosphate (S1P), whose role as a signalling lipid was discovered in Dr. Spiegel’s lab two decades ago. Dr. Spiegel notes that many physiological and pathophysiological processes, including cancer, inflammation and asthma, are regulated by S1P, and that the puzzle is how such a simple molecule as S1P can have such diverse roles has been resolved by the lab’s finding that S1P functions not only as a ligand for S1P receptors, but also inside cells to regulate histone deacetylase activity and gene transcription. They also developed a new paradigm of “inside-out” signalling by S1P which has important implications for proliferation, directed cell movement, angiogenesis, tumorigenesis, inflammation and allergic responses. The Spiegel/Milstien lab was the first to suggest that S1P plays important roles in allergic responses, including asthma and anaphylaxis, the incidence of which is rising worldwide especially in industrialized urban populations. The lab team are studying how S1P is formed and released, and how it acts at many cellular levels, including mast cells, the airway epithelium, airway smooth muscle and many immune cells. Since the actions of S1P on all of these cells could exacerbate allergic responses, the proteins that synthesize, release and respond to S1P offer plausible targets for a new generation of anti-inflammatory therapeutics.
In the study published in Nature Neuroscience, the researchers found that Sphk2″/” mice have lower levels of hippocampal sphingosine-1-phosphate, an endogenous HDAC inhibitor, and reduced histone acetylation, and display deficits in spatial memory and impaired contextual fear extinction. Thus, they say sphingosine-1-phosphate and SphK2 play specific roles in memory functions and FTY720 may not be an ideal agent for treating PTSD due to its side-effect profile (see below), what they’ve learned could be a start on developing new agents with greater specificity for the nuclear anti-HDAC action in the hippocampus that could potentially lead to useful adjuvant therapy to help facilitate control of aversive memories
The Multiple Sclerosis Trust describes fingolimod as a disease modifying drug currently used in treating persons with rapidly evolving severe relapsing remitting MS (two or more relapses a year), and for people who continue to have relapses despite treatment with one of the beta interferon drugs. It is also undergoing trials as a potential treatment for primary progressive MS. The trust notes that laboratory investigations have provided evidence that, in addition to its effect on the immune system, fingolimod may have neuroprotective and remyelinating properties in the brain and spinal cord.
The Multiple Sclerosis Coalition Emerging Therapies Collaborative observes that Gilenya is the first oral medication approved by the U.S. Food and Drug Administration (FDA) to modify disease activity in multiple sclerosis, and that it appears to prevent some potentially damaging T cells from leaving the lymph nodes. The result is that there are fewer T cells traveling into the central nervous system to do damage. It is not known yet whether fingolimod helps or protects the cells in a person’s CNS. The drug appears to work by binding to the surface of white blood cells (lymphocytes) in the immune system, thereby causing a large proportion of the lymphocytes to be retained in the lymph nodes, reducing the number that can reach the central nervous system and attack nerve cells in the brain and spinal cord. In addition, there is evidence that fingolimod, which is taken orally in capsule form, may have a direct effect on nerve cell damage and enhance the repair of myelin, which could have implications for people with progressive MS.
On the downside, the MS Trust says fingolimod may cause as a side effect a temporary bradycardia (decrease in the heart rate) and may be associated with atrioventricular block (a type of heart rhythm disorder), and that other common side effects include headache, liver enzyme increases, influenza, diahorrea, back pain, and cough. Fingolimod may also cause macular oedema (a swelling in the eye affecting vision).
LAst August, the FDA issued a public alert that a patient in Europe diagnosed with possible multiple sclerosis (MS) had developed a rare and serious brain infection after taking the drug Gilenya (fingolimod). This is the first case of progressive multifocal leukoencephalopathy (PML), reported following administration of Gilenya to a patient who had not previously received Tysabri (natalizumab), an MS drug associated with a higher risk of PML.
PML is a rare and serious brain infection caused by the John Cunningham (JC) virus that damages the fatty covering of the brain called myelin. PML usually causes death or severe disability. Gilenya is used to treat relapsing forms of MS, a nervous system disease that affects the brain and spinal cord. Novartis reports that approximately 71,000 patients worldwide have been treated with Gilenya.
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