sphingosine-kinase and Neurodegenerative-Diseases

Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P

Topics: Aldehyde-Lyases; Alzheimer Disease; Animals; Cerebrovascular Disorders; Clinical Trials as Topic; Dementia, Vascular; Drug Delivery Systems; Drug Evaluation, Preclinical; Fingolimod Hydrochloride; Humans; Infarction, Middle Cerebral Artery; Inflammation; Ischemic Stroke; Lysophospholipids; Mice; Mice, Knockout; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.

Topics: Alzheimer Disease; Central Nervous System; Ceramides; Eicosanoids; Forecasting; Homeostasis; Humans; Inflammation; Lipoxygenase; Lysophospholipids; Membrane Lipids; Models, Biological; Nerve Degeneration; Neurodegenerative Diseases; Neuroglia; Neurons; Parkinson Disease; Phosphotransferases (Alcohol Group Acceptor); Prostaglandin-Endoperoxide Synthases; Sphingolipids; Sphingosine

Sphingosine kinases (isoforms SK1 and SK2) catalyse the formation of a bioactive lipid, sphingosine 1-phosphate (S1P). S1P is a well-established ligand of a family of five S1P-specific G protein coupled receptors but also has intracellular signalling roles. There is substantial evidence to support a role for sphingosine kinases and S1P in health and disease. This review summarises recent advances in the area in relation to receptor-mediated signalling by S1P and novel intracellular targets of this lipid. New evidence for a role of each sphingosine kinase isoform in cancer, the cardiovascular system, central nervous system, inflammation and diabetes is discussed. There is continued research to develop isoform selective SK inhibitors, summarised here. Analysis of the crystal structure of SK1 with the SK1-selective inhibitor, PF-543, is used to identify residues that could be exploited to improve selectivity in SK inhibitor development for future therapeutic application.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Humans; Inflammation; Lysophospholipids; Models, Molecular; Neoplasms; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Receptors, G-Protein-Coupled; Signal Transduction; Sphingosine; Structure-Activity Relationship

Gene expression in eukaryotes depends on epigenetic changes that occur on both histones and DNA. Class I histone deacetylases (HDACs) are enzymes that remove acetyl groups from histones and other nuclear proteins, thereby inducing chromatin condensation and transcriptional repression. HDACs belong to a large family of enzymes that undergo posttranslational modifications after the activation of several intracellular pathways. However, the environmental stimuli that change nuclear HDAC functions remain largely unknown. New evidence has demonstrated that the lipid sphingosine-1-phosphate (S1P) inhibits the activity of HDAC1 and HDAC2. Both S1P and sphingosine kinase 2 (SphK2), the enzyme that synthesizes S1P, are assembled in corepressor complexes containing HDAC1 and HDAC2. S1P is among the few endogenous HDAC inhibitors that is synthesized in the nucleus in response to extracellular stimulation, and the first nuclear lipid associated with an epigenetic modification. The discovery of endogenous molecules that regulate HDAC activity in vivo has implications for the development of new therapeutic approaches for a host of human diseases, including cancer and neurodegenerative disorders.

Topics: Animals; Cell Nucleus; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Histone Deacetylase 1; Histone Deacetylase 2; Humans; Lysophospholipids; Neoplasms; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

Topics: Animals; Disease Models, Animal; Hypoxia-Inducible Factor 1, alpha Subunit; Mesenchymal Stem Cell Transplantation; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Rats

There is substantial evidence that the enzymes, sphingosine kinase 1 and 2, which catalyse the formation of the bioactive lipid sphingosine 1-phosphate, are involved in pathophysiological processes. In this chapter, we appraise the evidence that both enzymes are druggable and describe how isoform-specific inhibitors can be developed based on the plasticity of the sphingosine-binding site. This is contextualised with the effect of sphingosine kinase inhibitors in cancer, pulmonary hypertension, neurodegeneration, inflammation and sickling.

Topics: Anemia, Sickle Cell; Binding Sites; Enzyme Inhibitors; Humans; Hypertension, Pulmonary; Inflammation; Lysophospholipids; Neoplasms; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

Huntington disease (HD) is a genetic neurodegenerative disorder for which there is currently no cure and no way to stop or even slow the brain changes it causes. In the present study, we aimed to investigate whether FTY720, the first approved oral therapy for multiple sclerosis, may be effective in HD models and eventually constitute an alternative therapeutic approach for the treatment of the disease. Here, we utilized preclinical target validation paradigms and examined the in vivo efficacy of chronic administration of FTY720 in R6/2 HD mouse model. Our findings indicate that FTY720 improved motor function, prolonged survival and reduced brain atrophy in R6/2 mice. The beneficial effect of FTY720 administration was associated with a significant strengthening of neuronal activity and connectivity and, with reduction of mutant huntingtin aggregates, and it was also paralleled by increased phosphorylation of mutant huntingtin at serine 13/16 residues that are predicted to attenuate protein toxicity.

Topics: Animals; Brain; Cell Line; Disease Models, Animal; Fingolimod Hydrochloride; Huntington Disease; Immunoblotting; Immunohistochemistry; Male; Mice; Mice, Transgenic; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Propylene Glycols; Real-Time Polymerase Chain Reaction; Sphingosine

Kainic acid (KA) induces hippocampal cell death and astrocyte proliferation. There are reports that sphingosine kinase (SPHK)1 and sphingosine-1- phosphate (S1P) receptor 1 (S1P(1)) signaling axis controls astrocyte proliferation. Here we examined the temporal changes of SPHK1/S1P(1) in mouse hippocampus during KA-induced hippocampal cell death. Mice were killed at 2, 6, 24, or 48 h after KA (30 mg/kg) injection. There was an increase in Fluoro-Jade B-positive cells in the hippocampus of KA-treated mice with temporal changes of glial fibrillary acidic protein (GFAP) expression. The lowest level of SPHK1 protein expression was found 2h after KA treatment. Six hours after KA treatment, the expression of SPHK1 and S1P(1) proteins steadily increased in the hippocampus. In immunohistochemical analysis, SPHK1 and S1P(1) are more immunoreactive in astrocytes within the hippocampus of KA-treated mice than in hippocampus of control mice. These results indicate that SPHK1/S1P(1) signaling axis may play an important role in astrocytes proliferation during KA-induced excitotoxicity.

Topics: Animals; Astrocytes; Glial Fibrillary Acidic Protein; Hippocampus; Kainic Acid; Male; Mice; Mice, Inbred ICR; Nerve Tissue Proteins; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid