title: Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis.
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.
authors.affiliation: Institute of Biotechnology and Biomedicine, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Pifarre
authors.forename: Judith
authors.initials: J
authors.lastname: Prado
authors.forename: María Antonia
authors.initials: MA
authors.lastname: Baltrons
authors.forename: Merce
authors.initials: M
authors.lastname: Giralt
authors.forename: Pere
authors.initials: P
authors.lastname: Gabarro
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.forename: Agustina
authors.initials: A
authors.lastname: Garcia
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology; D006023:Glycoproteins / Q000009:adverse effects; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D016900:Neurofilament Proteins / Q000378:metabolism; D010446:Peptide Fragments / Q000009:adverse effects; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology*; D013450:Sulfones / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D017252:CD3 Complex; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D016900:Neurofilament Proteins; D010446:Peptide Fragments; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; C445081:myelin oligodendrocyte glycoprotein (35-55); C051774:neurofilament protein H; D018799:Intercellular Adhesion Molecule-1; D000068677:Sildenafil Citrate