Prophylactic versus Therapeutic Fingolimod: Restoration of Presynaptic Defects in Mice Suffering from Experimental Autoimmune Encephalomyelitis
| Autor: | Cristina Padolecchia, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Silvia Di Prisco, Mario Marchi, Giambattista Bonanno, Massimo Grilli, Tommaso Bonfiglio, Anna Pittaluga, Guendalina Olivero, Marco Milanese, Elisa Merega |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Genetics and Molecular Biology (all) Central Nervous System Physiology Encephalomyelitis lcsh:Medicine Administration Oral Pharmacology Inbred C57BL Biochemistry Nervous System Hippocampus Mice 0302 clinical medicine Medicine and Health Sciences Public and Occupational Health lcsh:Science gamma-Aminobutyric Acid Mammals Cerebral Cortex Multidisciplinary Secretory Pathway Experimental autoimmune encephalomyelitis Glutamate receptor Neurochemistry Neurotransmitters Fingolimod Vaccination and Immunization Electrophysiology medicine.anatomical_structure Spinal Cord Cell Processes Organ Specificity Administration Vertebrates GABAergic Female Drug Glutamate Anatomy Cell activation Neuroglia Immunosuppressive Agents medicine.drug Research Article Oral l Autoimmune Encephalomyelitis Encephalomyelitis Autoimmune Experimental Central nervous system Immunology Neurophysiology Glutamic Acid Rodents Exocytosis Dose-Response Relationship 03 medical and health sciences Experimental Fingolimod Hydrochloride medicine Animals Dose-Response Relationship Drug business.industry Prophylaxis lcsh:R Organisms Biology and Life Sciences Cell Biology medicine.disease Mice Inbred C57BL Neuroanatomy 030104 developmental biology Agricultural and Biological Sciences (all) Amniotes Synapses lcsh:Q Preventive Medicine business Biochemistry Genetics and Molecular Biology (all) 030217 neurology & neurosurgery Autoimmune Neuroscience Synaptosomes |
| Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 1, p e0170825 (2017) |
| ISSN: | 1932-6203 |
| Popis: | Fingolimod, the first oral, disease-modifying therapy for MS, has been recently proposed to modulate glutamate transmission in the central nervous system (CNS) of mice suffering from Experimental Autoimmune Encephalomyelitis (EAE) and in MS patients. Our study aims at investigating whether oral fingolimod recovers presynaptic defects that occur at different stages of disease in the CNS of EAE mice. In vivo prophylactic (0.3 mg/kg for 14 days, from the 7th day post immunization, d.p.i, the drug dissolved in the drinking water) fingolimod significantly reduced the clinical symptoms and the anxiety-related behaviour in EAE mice. Spinal cord inflammation, demyelination and glial cell activation are markers of EAE progression. These signs were ameliorated following oral fingolimod administration. Glutamate exocytosis was shown to be impaired in cortical and spinal cord terminals isolated from EAE mice at 21 ± 1 d.p.i., while GABA alteration emerged only at the spinal cord level. Prophylactic fingolimod recovered these presynaptic defects, restoring altered glutamate and GABA release efficiency. The beneficial effect occurred in a dose-dependent, region-specific manner, since lower (0.1-0.03 mg/kg) doses restored, although to a different extent, synaptic defects in cortical but not spinal cord terminals. A delayed reduction of glutamate, but not of GABA, exocytosis was observed in hippocampal terminals of EAE mice at 35 d.p.i. Therapeutic (0.3 mg/kg, from 21 d.p.i. for 14 days) fingolimod restored glutamate exocytosis in the cortex and in the hippocampus of EAE mice at 35 ± 1 d.p.i. but not in the spinal cord, where also GABAergic defects remained unmodified. These results improve our knowledge of the molecular events accounting for the beneficial effects elicited by fingolimod in demyelinating disorders. |
| Databáze: | OpenAIRE |
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