Oral administration of the KATP channel opener diazoxide ameliorates disease progression in a murine model of multiple sclerosis

Journal of Neuroinflammation

Marco Pugliese¹  Nicole Mahy¹  Manuel J Rodríguez¹  Javier Gimeno-Bayon¹  Andrea Pastén-Zamorano²  Pilar Mancera²  Juan F Espinosa-Parrilla²  Noemí Virgili² 

[1] Unitat de Bioquímica i Biologia Molecular, Departament de Ciències Fisiològiques I, Facultat de Medicina, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), c/Casanova 143, 08036 Barcelona, Spain;Neurotec Pharma SL, Bioincubadora PCB-Santander, Parc Científic de Barcelona, c/Josep Samitier 1-5, 08028 Barcelona, Spain

关键词: neuroprotection;    multiple sclerosis;    microglia;    K_ATP channel;    experimental autoimmune encephalomyelitis;    Diazoxide;   

Others  :  1213033
DOI  :  10.1186/1742-2094-8-149

 received in 2011-08-05, accepted in 2011-11-02,  发布年份 2011

【 摘 要 】

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 (K_ATP) 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_ATP 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 (IFNγ)-activated microglial cells. EAE was induced in C57BL/6J mice by immunization with myelin oligodendrocyte glycoprotein peptide (MOG_35-55). 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-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.

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.

【 授权许可】

   
2011 Virgili et al; licensee BioMed Central Ltd.

【 图 表 】

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