Species-specific accumulation of ceramides in cerebrospinal fluid from encephalomyeloradiculoneurpathy patients associated with peripheral complement activation: A pilot study |
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| Institution: | 1. Department of Neurology and Neuroscience, Fujita Health University Hospital, Aichi, Japan;2. Faculty of Pharmacy, Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science and Frontier Research Center for Advanced Material and Life Science, Hokkaido University, Hokkaido, Japan;1. Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;2. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China;3. Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA;4. Biochemistry and Cell Biology Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA;1. Department of Pathology and Laboratory Medicine, University of Cincinnati Medical School, Cincinnati, OH, United States of America;2. Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee Women''s Research Institute, Pittsburgh, PA, United States of America;3. Center for Research in Perinatal Outcomes, Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL, United States of America;4. Center for Research in Perinatal Outcomes, Department of Obstetrics and Gynecology, University of Florida, Gainesville, FL, United States of America;1. Laboratory for Innovative Therapy Research, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan;2. Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan;3. Project Management Department, Shionogi & Co., Ltd, 8F (Reception) / 9F, Nissay Yodoyabashi East, 3-13, Imabashi 3-chome, Chuo-ku, Osaka 541-0042, Japan;4. Research Planning Department, Shionogi & Co., Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan;1. Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirao Preto, University of São Paulo, Brazil;2. Núcleo de Pesquisa em Produtos Naturais e Sintéticos (NPPNS), Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 14040-903, Brazil;3. Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, São Paulo, Brazil;4. Head and Neck Surgery Department, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas HCFMUSP, Faculdade de Medicina (LIM28), Universidade de São Paulo, São Paulo, Brazil;5. CEPID-FAPESP, Center for Cell Based Therapy, Regional Blood Center of Ribeirão Preto, SP, Brazil |
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| Abstract: | Glycolipids are now known to be rapidly converted to mediators for inflammatory reactions or to signaling molecules that control inflammatory events in the nervous system. The present study aimed to explore whether disturbed glycolipids metabolism in the nervous system is present in patients with a neuroinflammatory disorder, encephalo-myelo-radiculo-neuropathy (EMRN), because most EMRN patients have been reported to exhibit autoantibodies against neutral glycolipids. Although molecular pathogenesis of this disorder remains unknown, we tried to search the immunochemical abnormalities in this disorder. ELISA for activated peripheral C5 complement and mass spectrometry analysis of cerebrospinal fluid clearly disclosed a significant upregulation of active C5 complement, C5a levels in sera as well as a significant accumulation of species-specific ceramides but not sphingomyelin in cerebrospinal fluid from EMRN patients. Furthermore, we confirmed the occurrence of anti-neutral glycolipids antibodies in all EMRN patients.Thus, the present study might indicate the pathophysiology of this disorder is the dysregulation of glycolipids metabolism and abnormal production of autoantibodies against neutral glycolipids resulting in the abnormal complement activation, although molecular basis for these sphingolipids dysregulation and the occurrence of autoantibodies against glycolipids remains to be elucidated at present. The present study implicates a new therapeutic strategy employing anti-ceramide and/or anti-complement therapy for this disorder. |
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