Oral administration of the K<sub>ATP </sub>channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis
<p>Abstract</p> <p>Background</p> <p>Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2011-11-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://www.jneuroinflammation.com/content/8/1/149 |
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| author | Mahy Nicole Rodríguez Manuel J Gimeno-Bayon Javier Pastén-Zamorano Andrea Mancera Pilar Espinosa-Parrilla Juan F Virgili Noemí Pugliese Marco |
| author_facet | Mahy Nicole Rodríguez Manuel J Gimeno-Bayon Javier Pastén-Zamorano Andrea Mancera Pilar Espinosa-Parrilla Juan F Virgili Noemí Pugliese Marco |
| author_sort | Mahy Nicole |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (K<sub>ATP</sub>) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of K<sub>ATP </sub>channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.</p> <p>Methods</p> <p>Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNγ)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG<sub>35-55</sub>). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration.</p> <p>Results</p> <p>Diazoxide inhibited <it>in vitro </it>nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord.</p> <p>Conclusion</p> <p>Taken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.</p> |
| first_indexed | 2024-12-10T17:49:06Z |
| format | Article |
| id | doaj.art-18470851e78c4a3e8a555d81f66d5dfe |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-10T17:49:06Z |
| publishDate | 2011-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-18470851e78c4a3e8a555d81f66d5dfe2022-12-22T01:39:07ZengBMCJournal of Neuroinflammation1742-20942011-11-018114910.1186/1742-2094-8-149Oral administration of the K<sub>ATP </sub>channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosisMahy NicoleRodríguez Manuel JGimeno-Bayon JavierPastén-Zamorano AndreaMancera PilarEspinosa-Parrilla Juan FVirgili NoemíPugliese Marco<p>Abstract</p> <p>Background</p> <p>Multiple Sclerosis (MS) is an acquired inflammatory demyelinating disorder of the central nervous system (CNS) and is the leading cause of nontraumatic disability among young adults. Activated microglial cells are important effectors of demyelination and neurodegeneration, by secreting cytokines and others neurotoxic agents. Previous studies have demonstrated that microglia expresses ATP-sensitive potassium (K<sub>ATP</sub>) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of K<sub>ATP </sub>channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS.</p> <p>Methods</p> <p>Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNγ)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG<sub>35-55</sub>). Mice were orally treated daily with diazoxide or vehicle for 15 days from the day of EAE symptom onset. Treatment starting at the same time as immunization was also assayed. Clinical signs of EAE were monitored and histological studies were performed to analyze tissue damage, demyelination, glial reactivity, axonal loss, neuronal preservation and lymphocyte infiltration.</p> <p>Results</p> <p>Diazoxide inhibited <it>in vitro </it>nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) production and inducible nitric oxide synthase (iNOS) expression by activated microglia without affecting cyclooxygenase-2 (COX-2) expression and phagocytosis. Oral treatment of mice with diazoxide ameliorated EAE clinical signs but did not prevent disease. Histological analysis demonstrated that diazoxide elicited a significant reduction in myelin and axonal loss accompanied by a decrease in glial activation and neuronal damage. Diazoxide did not affect the number of infiltrating lymphocytes positive for CD3 and CD20 in the spinal cord.</p> <p>Conclusion</p> <p>Taken together, these results demonstrate novel actions of diazoxide as an anti-inflammatory agent, which might contribute to its beneficial effects on EAE through neuroprotection. Treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention in ameliorating MS disease.</p>http://www.jneuroinflammation.com/content/8/1/149Diazoxideexperimental autoimmune encephalomyelitisK<sub>ATP </sub>channelmicrogliamultiple sclerosisneuroprotection |
| spellingShingle | Mahy Nicole Rodríguez Manuel J Gimeno-Bayon Javier Pastén-Zamorano Andrea Mancera Pilar Espinosa-Parrilla Juan F Virgili Noemí Pugliese Marco Oral administration of the K<sub>ATP </sub>channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis Journal of Neuroinflammation Diazoxide experimental autoimmune encephalomyelitis K<sub>ATP </sub>channel microglia multiple sclerosis neuroprotection |
| title | Oral administration of the K<sub>ATP </sub>channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis |
| title_full | Oral administration of the K<sub>ATP </sub>channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis |
| title_fullStr | Oral administration of the K<sub>ATP </sub>channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis |
| title_full_unstemmed | Oral administration of the K<sub>ATP </sub>channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis |
| title_short | Oral administration of the K<sub>ATP </sub>channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis |
| title_sort | oral administration of the k sub atp sub channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis |
| topic | Diazoxide experimental autoimmune encephalomyelitis K<sub>ATP </sub>channel microglia multiple sclerosis neuroprotection |
| url | http://www.jneuroinflammation.com/content/8/1/149 |
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