Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/20963
Title: Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis
Author: Virgili, Noemi
Espinosa Parrilla, Juan Francisco
Mancera, Pilar
Pasten-Zamorano, Andrea
Gimeno-Bayon, Javier
Rodríguez Allué, Manuel José
Mahy Gehenne, Josette Nicole
Pugliese, Marco
Keywords: Esclerosi múltiple
Assaigs clínics de medicaments
Multiple sclerosis
Drug testing
Issue Date: 2-Oct-2011
Publisher: BioMed Central Ltd
Abstract: Background 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 (KATP) channels and its pharmacological activation can provide neuroprotective and anti-inflammatory effects. In this study, we have examined the effect of oral administration of KATP channel opener diazoxide on induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Methods Anti-inflammatory effects of diazoxide were studied on lipopolysaccharide (LPS) and interferon gamma (IFNy)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). 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. Results Diazoxide inhibited in vitro nitric oxide (NO), tumor necrosis factor alpha (TNF-¿) 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. Conclusion 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.
Note: Reproducció del document publicat a: http://dx.doi.org/10.1186/1742-2094-8-149
It is part of: Journal of Neuroinflammation 2011, 8:149
URI: http://hdl.handle.net/2445/20963
ISSN: 1742-2094
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)

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