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Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis

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Abstract

Cyclic GMP (cGMP)-mediated pathways regulate inflammatory responses in immune and CNS cells. Recently, cGMP phosphodiesterase inhibitors such as sildenafil, commonly used to treat sexual dysfunction in humans including multiple sclerosis (MS) patients, have been reported to be neuroprotective in animal models of stroke, Alzheimer’s disease, and focal brain lesion. In this work, we have examined if sildenafil ameliorates myelin oligodendrocyte glycoprotein peptide (MOG35–55)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show for the first time that treatment with sildenafil after disease onset markedly reduces the clinical signs of EAE by preventing axonal loss and promoting remyelination. Furthermore, sildenafil decreases CD3+ leukocyte infiltration and microglial/macrophage activation in the spinal cord, while increasing forkhead box transcription factor 3-expressing T regulatory cells (Foxp3 Tregs). However, sildenafil treatment did not significantly affect MOG35–55-stimulated proliferation or release of Th1/Th2 cytokines in splenocytes but decreased ICAM-1 in spinal cord infiltrated cells. The presence of reactive astrocytes forming scar-like structures around infiltrates was enhanced by sildenafil suggesting a possible mechanism for restriction of leukocyte spread into healthy parenchyma. These results highlight novel actions of sildenafil that may contribute to its beneficial effects in EAE and suggest that treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention to ameliorate MS neuropathology.

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Acknowledgments

This work was supported by grants SAF2007-64164 and SGR2005-939 to AG and SAF2008-00435 and RETICS (REEM, RD07/0060/0002) to JH. We thank Mar Castillo and David Lligé for technical support and Dr. Dolores Jaraquemada for helpful discussion.

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Authors and Affiliations

  1. Institute of Biotechnology and Biomedicine, Universitat Autonoma de Barcelona, 08193, Bellaterra, Spain

    Paula Pifarre, Judith Prado, María Antonia Baltrons, Pere Gabarro & Agustina Garcia

  2. Department of Biochemistry and Molecular Biology, Universitat Autonoma de Barcelona, Bellaterra, Spain

    María Antonia Baltrons & Agustina Garcia

  3. Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Universitat Autonoma de Barcelona, Bellaterra, Spain

    Merce Giralt & Juan Hidalgo

  4. Department of Anesthesiology, University of Illinois, Chicago, IL, USA

    Douglas L. Feinstein

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  1. Paula Pifarre
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  2. Judith Prado
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  3. María Antonia Baltrons
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  4. Merce Giralt
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  7. Juan Hidalgo
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  8. Agustina Garcia
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Corresponding author

Correspondence to Agustina Garcia.

Electronic supplementary material

Supplemental Fig. 1

. BSA-immunized mice do not present demyelination or axonal loss. Spinal cord sections from BSA-immunized mice 26 dpi (n = 4), treated or not with sildenafil for 8 days, stained with LFB (a) or Bielschowsky (b) (JPEG 638 kb)

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Pifarre, P., Prado, J., Baltrons, M.A. et al. Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis. Acta Neuropathol 121, 499–508 (2011). https://doi.org/10.1007/s00401-010-0795-6

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  • DOI: https://doi.org/10.1007/s00401-010-0795-6

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