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Diazoxide Attenuates Autoimmune Encephalomyelitis and Modulates Lymphocyte Proliferation and Dendritic Cell Functionality

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Abstract

Activation of mitochondrial ATP-sensitive potassium (KATP) channels is postulated as an effective mechanism to confer cardio and neuroprotection, especially in situations associated to oxidative stress. Pharmacological activation of these channels inhibits glia-mediated neuroinflammation. In this way, diazoxide, an old-known mitochondrial KATP channel opener, has been proposed as an effective and safe treatment for different neurodegenerative diseases, demonstrating efficacy in different animal models, including the experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple Sclerosis. Although neuroprotection and modulation of glial reactivity could alone explain the positive effects of diazoxide administration in EAE mice, little is known of its effects on the immune system and the autoimmune reaction that triggers the EAE pathology. The aim of the present work was to study the effects of diazoxide in autoimmune key processes related with EAE, such as antigen presentation and lymphocyte activation and proliferation. Results show that, although diazoxide treatment inhibited in vitro and ex-vivo lymphocyte proliferation from whole splenocytes it had no effect in isolated CD4+ T cells. In any case, treatment had no impact in lymphocyte activation. Diazoxide can also slightly decrease CD83, CD80, CD86 and major histocompatibility complex class II expression in cultured dendritic cells, demonstrating a possible role in modulating antigen presentation. Taken together, our results indicate that diazoxide treatment attenuates autoimmune encephalomyelitis pathology without immunosuppressive effect.

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Acknowledgments

We thank Dr. Pablo Villoslada and the members of the Neuroimmunology Group from Hospital Clínic-IDIBAPS, Barcelona, Spain for their scientific and technical assistance. We also thank Dr. Javier Bustos from Neurotec Pharma and Dr. Georgina Sorrosal, Dr. Clara Campàs, Dr. Mercè de Frias from Advancell for their critical review of the manuscript. MJR work is supported by grant IPT-2012-0614-010000 from the Ministerio de Economia, and by grant 2009 SGR1380 from the Generalitat de Catalunya, Spain.

Competing Interests

NV, PM, MP, JFEP have applied for a PCT application “Diazoxide for use in the treatment of a central nervous system (CNS) autoimmune demyelinating disease” (application number PCT/EP2011/050049). MP is CEO in Neurotec Pharma and also holds shares in the company. NV, PM, BW, JFEP are employed in Neurotec Pharma. CC, AW, MJR and CID declares no competing interests.

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Authors and Affiliations

  1. Neurotec Pharma S.L., Bioincubadora PCB-Santander, Parc Científic de Barcelona, Barcelona, Spain

    N. Virgili, P. Mancera, B. Wappenhans, J. F. Espinosa-Parrilla & M. Pugliese

  2. Institute for Medical Immunology, Charité-Universitätmedizin Berlin, Berlin, Germany

    C. Chanvillard, A. Wegner & C. Infante-Duarte

  3. Departament de Ciències Fisiològiques I, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

    M. J. Rodríguez & M. Pugliese

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  1. N. Virgili
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Correspondence to J. F. Espinosa-Parrilla.

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J. F. Espinosa-Parrilla and M. Pugliese equally contributing senior authors

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Virgili, N., Mancera, P., Chanvillard, C. et al. Diazoxide Attenuates Autoimmune Encephalomyelitis and Modulates Lymphocyte Proliferation and Dendritic Cell Functionality. J Neuroimmune Pharmacol 9, 558–568 (2014). https://doi.org/10.1007/s11481-014-9551-3

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