Artículos de revistas
Sildenafil (viagra®) Down Regulates Cytokines And Prevents Demyelination In A Cuprizone-induced Ms Mouse Model
Registro en:
Cytokine. , v. 60, n. 2, p. 540 - 551, 2012.
10434666
10.1016/j.cyto.2012.06.011
2-s2.0-84866770267
Autor
Nunes A.K.D.S.
Raposo C.
Luna R.L.D.A.
Cruz-Hofling M.A.D.
Peixoto C.A.
Institución
Resumen
Sildenafil induces cGMP accumulation through phosphodiesterase-5 (PDE5) inhibition. cGMP-pathways protect oligodendrocytes and modulate astroglial and microglial reactions. Microglia and astrocytes play an important role in perpetuating multiple sclerosis (MS), a chronic inflammatory disease characterized by demyelination. Therefore, sildenafil can be a potential tool for MS treatment. The present study investigated the effects of sildenafil on the myelin structure and astrocyte/microglia-mediated neuroinflammation in an animal model of MS. Cuprizone-induced demyelination and neuroinflammation in rodents has been widely used as a model for MS. Herein, five male C57BL/6 mice (7-10. weeks old) were used per group. Over a 4-week period, the different groups received the following: (1) cuprizone (0.2%) mixed into the chow; (2) cuprizone in the chow and sildenafil (Viagra®; 3, 25 or 50. mg/kg) in the drinking water; or (3) pure chow and water (control group). Cerebella were analyzed using transmission electron microscopy, western blotting, immunohistochemistry and luxol fast blue staining. Cuprizone induced tissue damage, with an increase in GFAP, Iba-1 and COX-2 and demyelination in comparison to the control group. However, cuprizone did not affect the expression of cytokines (TNF-α, IFN-γ, IL-1β and IL-2). Sildenafil reduced GFAP (25 and 50. mg/kg) and Iba-1 expression (25. mg/kg) in comparison to the cuprizone group, indicating the modulation of astrocytes and microglia, respectively. Sildenafil preserved myelin and axons ultrastructure and strongly reduced IFN-γ, TNF-α, IL-1β, IL-2 and COX-2 expression in comparison to the control and/or cuprizone groups. The results demonstrate a protective effect of sildenafil in the cerebellum. Thus, well-designed clinical trials may demonstrate that the oral administration of sildenafil can be suitable for individuals with MS and other neuroinflammatory/neurodegenerative diseases, providing additional benefits to current treatments. © 2012 Elsevier Ltd. 60 2 540 551 Block, M.L., Zecca, L., Hong, J.S., Microglia-mediated neurotoxicity uncovering the molecular mechanisms (2007) Nat Rev Neurosci, 8, pp. 57-69 McGeer, E.G., McGeer, P.L., The role of anti-inflammatory agents in Parkinson's disease (2007) CNS Drugs, 21, pp. 789-797 Trapp, B.D., Nave, K.A., Multiple sclerosis: an immune or neurodegenerative disorder? (2008) Annu Rev Neurosci, 31, pp. 247-269 Moharregh-Khiabani, D., Blank, A., Skripuletz, T., Miller, E., Kotsiari, A., Gudi, V., Effects of fumaric acids on cuprizone induced central nervous system de- and remyelination in the mouse (2010) PLoS One, 5, pp. 117-169 Noseworthy, J.H., Lucchinetti, C., Rodriguez, M., Weinshenker, B.G., Multiple sclerosis (2000) New Engl J Med, 343, pp. 938-952 Trapp, B.D., Peterson, J., Ransohoff, R.M., Rudick, R., Mörk, S., Bö, L., Axonal transaction in the lesions of multiple sclerosis (1998) New Engl J Med, 338, pp. 278-285 Gao, Z., Tsirka, S.E., Animal Models of MS reveal multiple roles of microglia in disease pathogenesis (2011) Neurol Res Int, 2011, p. 383087 Kipp, M., Norkus, A., Krauspe, B., Clarner, T., Berger, K., van der Valk, P., The hippocampal fimbria of cuprizone-treated animals as a structure for studying neuroprotection in multiple sclerosis (2011) Inflamm Res, 60, pp. 723-726 Frank-Cannon, T.C., Alto, L.T., McAlpine, F.E., Tansey, M.G., Does neuroinflammation fan the flame in neurodegenerative diseases? (2009) Mol Neurodegener, 4, p. 47 Mrak, R.E., Griffin, W.S., Glia and their cytokines in progression of neurodegeneration (2005) Neurobiol Aging, 26, pp. 349-354 Johnson, K.P., Brooks, B.R., Ford, C.C., Goodman, A., Guarnaccia, J., Lisak, R.P., Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6years. Copolymer 1 Multiple Sclerosis Study Group (2000) Mult Scler, 6, pp. 255-266 Reder, A.T., Ebers, G.C., Traboulsee, A., Li, D., Langdon, D., Goodin, D.S., Cross-sectional study assessing long-term safety of interferon-beta-1b for relapsing-remitting MS (2010) Neurology, 74, pp. 1877-1885 Yoshioka, A., Yamaya, Y., Saiki, S., Kanemoto, M., Hirose, G., Pleasure, D., Cyclic GMP/cyclic GMP-dependent protein kinase system prevents excitotoxicity in an immortalized oligodendroglial cell line (2000) J Neurochem, 74, pp. 633-640 Huizinga, R., van der Star, B.J., Kipp, M., Jong, R., Gerritsen, W., Clarner, T., Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis (2012) Glia, 60, pp. 422-431 Meda, L., Cassatella, M.A., Szendrei, G.I., Otvos, L., Baron, P., Villalba, M., Activation of microglial cells by ß-amyloid protein and interferon-gamma (1995) Nature, 374, pp. 647-650 Pifarré, P., Prado, J., Baltrons, M.A., Giralt, M., Gabarro, P., Feinstein, D.L., Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis (2011) Acta Neuropathol, 121, pp. 499-508 Rosenberg, G.A., Neurological diseases in relation to the blood-brain barrier (2012) J Cereb Blood Flow Metab Puzzo, D., Sapienza, S., Arancio, O., Palmeri, A., Role of phosphodiesterase 5 in synaptic plasticity and memory (2008) Neuropsychiatr Dis Treat, 4, pp. 371-387 Prickaerts, J., van Staveren, W.C., Sik, A., Markerink-van Ittersum, M., Niewöhner, U., van der Staay, F.J., Effects of two selective phosphodiesterase type 5 inhibitors, sildenafil and vardenafil, on object recognition memory and hippocampal cyclic GMP levels in the rat (2002) Neuroscience, 113, pp. 351-361 Boccia, M.M., CM. Effects of oxytocin and an oxytocin receptor antagonist on retention of a nose-poke habituation response in mice (1999) Acta Physiol Pharmacol Ther Latinoam, 49, pp. 155-160 Wakita, H., Tomimoto, H., Akiguchi, I., Lin, J.X., Ihara, M., Ohtani, R., Ibudilast protect against white matter damage under chronic cerebral hypoperfusion in the rat (2003) Brain Res, 992, pp. 53-59 Manson, S.C., Burke, G., Voets, N., Palace, J., Matthews, P.M., Effect of sildenafil citrate on CBF and BOLD activation in multiple sclerosis patients (2005), 21st congress of the European Committee for the Treatment and Research in Multiple Sclerosis Poster No. 237 Thessaloniki, GreeceZhang, L., Yu, W., Schroedter, I., Kong, J., Vrontakis, M., Galanin transgenic mice with elevated circulating galanin levels alleviate demyelination in a cuprizone-induced MS mouse model (2012) PLoS One, 7, pp. e33901 Silvestroff, L., Bartucci, S., Pasquini, J., Franco, P., Cuprizone-induced demyelination in the rat cerebral cortex and thyroid hormone effects on cortical remyelination (2012) Exp Neurol Zhao, L., Mason, N.A., Strange, J.W., Walker, H., Wilkins, M.R., Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic peptide activity (2003) Circulation, 107, pp. 234-237 Saraiva, K.L., Silva, A.K., Wanderley, M.I., De Araújo, A.A., De Souza, J.R., Peixoto, C.A., Chronic treatment with sildenafil stimulates Leydig cell and testosterone secretion (2009) Int J Exp Pathol, 90, pp. 454-462 Saraiva, K.L., Silva, V.A., Dias, E.S., Peixoto, C.A., Morphological changes in the testis induced by diethylcarbamazine (2006) Reprod Toxicol, 22, pp. 754-759 Riccitelli, G., Rocca, M.A., Pagani, E., Martinelli, V., Radaelli, M., Falini, A., Mapping regional grey and white matter atrophy in relapsing-remitting multiple sclerosis (2012) Mult Scler Shields, S.D., Cheng, X., Gasser, A., Saab, C.Y., Tyrrell, L., Eastman, E.M., A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis (2012) Ann Neurol, 71, pp. 186-194 Skripuletz, T., Bussmann, J.H., Gudi, V., Koutsoudaki, P.N., Pul, R., Moharregh-Khiabani, D., Cerebellar cortical demyelination in the murine cuprizone model (2010) Brain Pathol, 20, pp. 301-312 Zhang, R.L., Zhang, Z., Zhang, L., Wang, Y., Zhang, C., Chopp, M., Delayed treatment with Sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia (2006) J Neurosci Res, 83, pp. 1213-1219 Zhang, Y.Q., Rodesch, C.K., Broadie, K., Living synaptic vesicle marker: synaptotagmin-GFP (2002) Genesis, 34, pp. 142-145 Kulkarni, S.K., Patil, C.S., Phosphodiesterase 5 enzyme and its inhibitors: update on pharmacological and therapeutical aspects (2004) Methods Find Exp Clin Pharmacol, 26, pp. 789-799 Shimizu-Albergine, M., Rybalkin, S.D., Rybalkina, I.G., Feil, R., Wolfsgruber, W., Hofmann, F., Individual cerebellar Purkinje cells express different cGMP phosphodiesterases (PDEs): in vivo phosphorylation of cGMP-specific PDE (PDE5) as an indicator of cGMP-dependent protein kinase (PKG) activation (2003) J Neurosci, 23, pp. 6452-6459 Rosengren, L.E., Lycke, J., Andersen, O., Glial fibrillary acidic protein in CSF of multiple sclerosis patients: relation to neurological deficit (1995) J Neurol Sci, 133, pp. 61-65 Petzold, A., Eikelenboom, M.J., Gyeric, D., Markers for differential glial cell responses in multiple sclerosis: clinical and pathological correlations (2002) Brain, 125, pp. 1462-1473 Tani, M., Glabinski, A.R., Tuohy, V.K., Stoler, M.H., Estes, M.L., Ransohoff, R.M., In situ hybridization analysis of glial fibrillary acidic protein mRNA reveals evidence of biphasic astrocyte activation during acute experimental autoimmune encephalomyelitis (1996) Am J Pathol, 148, pp. 889-896 Voskuhi, R.R., Peterson, R.S., Song, B., Ao, Y., Morales, L.B., Tiwari-Woodruff, S., Reactive astrocytes form scar-like perivascular barriers to leukocutes during adaptative immune inflammation of the CNS (2009) J Neurosci, 29, pp. 11511-11522 Glabinski, A.R., Tani, M., Strieter, R.M., Tuohy, V.K., Ransohoff, R.M., Synchronous synthesis of alpha- and beta-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis (1997) Am J Pathol, 150, pp. 617-630 Ambrosini, E., Remoli, M.E., Giacomini, E., Rosicarelli, B., Serafini, B., Lande, R., Astrocytes produce dendritic cell-attracting chemokines in vitro and in multiple sclerosis lesions (2005) J Neuropathol Exp Neurol, 64, pp. 706-715 Hardin-Pouzet, H., Krakowski, M., Bourbonnière, L., Didier-Bazes, M., Tran, E., Owens, T., Glutamate metabolism is down-regulated in astrocytes during experimental allergic encephalomyelitis (1997) Glia, 20, pp. 79-85 Korn, T., Magnus, T., Jung, S., Autoantigen specific T cells inhibit glutamate uptake in astrocytes by decreasing expression of astrocytic glutamate transporter GlAST: a mechanism mediated by tumor necrosis factor-alpha (2005) FASEB J, 19, pp. 1878-1880 Pitt, D., Werner, P., Raine, C.S., Glutamate excitotoxicity in a model of multiple sclerosis (2000) Nat Med, 6, pp. 67-70 Micu, J., Jiang, Q., Coderre, E., Ridsdale, A., Zhang, L., Woulfe, J., NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia (2006) Nature, 439, pp. 988-992 Back, S.A., Tuohy, T.M., Chen, H., Wallingford, N., Craig, A., Struve, J., Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation (2005) Nat Med, 11 (9), pp. 966-972. , Epub 2005 August 7 Toft-Hansen, H., Füchtbauer, L., Owens, T., Inhibition of reactive astrocytosis in established experimental autoimmune encephalomyelitis favors infiltration by myeloid cells over T cells and enhances severity of disease (2011) Glia, 59, pp. 166-176 Bannerman, P., Hahn, A., Soulika, A., Gallo, V., Pleasure, D., Astrogliosis in EAE spinal cord: derivation from radial glia, and relationships to oligodendroglia (2007) Glia, 55, pp. 57-64 Pifarré, P., Prado, J., Giralt, M., Molinero, A., Hidalgo, J., Garcia, A., Cyclic GMP phosphodiesterase inhibition alters the glial inflammatory response, reduces oxidative stress and cell death and increases angiogenesis following focal brain injury (2010) J Neurochem, 112, pp. 807-817 Rott, O., Fleischer, B., Cash, E., Interleukin-10 prevents experimental allergic encephalomyelitis in rats (1994) Eur J Immunol, 24, pp. 1434-1440 Stevens, D.B., Gould, K.E., Swanborg, R.H., Transforming growth factor-beta 1 inhibits tumor necrosis factor-alpha/lymphotoxin production and adoptive transfer of disease by effector cells of autoimmune encephalomyelitis (1994) J Neuroimmunol, 51, pp. 77-83 Kreutzberg, G.W., Microglia: a sensor for pathological events in the CNS (1996) Trends Neurosci, 19, pp. 312-318 Khoshakhlagh, P., Bahrololoumi-Shapourabadi, M., Mohammadirad, A., Ashtaral-Nakhai, L., Minaie, B., Abdollahi, M., Beneficial effect of phosphodiesterase-5 inhibitor in experimental inflammatory bowel disease molecular evidence for involvement of oxidative stress (2007) Toxicol Mech Methods, 17 (5), pp. 281-288 Suzumura, A., Ito, A., Yoshikawa, M., Sawada, M., Ibudilast suppressesTNF alpha production by glial cells functioning mainly as type III phosphodiesterase inhibitor in the CNS (1999) Brain Res, 837, pp. 203-212 da Cruz-Höfling, M.A., Rapôso, C., Verinaud, L., Zago, G.M., Neuroinflammation and astrocytic reaction in the course of Phoneutria nigriventer (armed-spider) blood-brain barrier (BBB) opening (2009) Neurotoxicology, 30, pp. 636-646 Palumbo, M.L., Trinchero, M.F., Zorrilla-Zubilete, M.A., Schinder, A.F., Genaro, A.M., Glatiramer acetate reverts stress-induced alterations on adult neurogenesis and behavior. Involvement of Th1/Th2 balance (2011) Behav Brain Res, 218, pp. 121-128 Zhao, S., Zhang, L., Lian, G., Wang, X., Zhang, H., Yao, X., Sildenafil attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NF-κB signaling pathways in N9 microglia (2011) Int Immunopharmacol, 11, pp. 468-474 Wang, L., Chopp, M., Szalad, A., Liu, Z., Bolz, M., Alvarez, F.M., Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice (2011) Neuroscience, 193, pp. 399-410 Benjamins, J.A., Nedelkoska, L., Cyclic GMP-dependent pathways protect differentiated oligodendrocytes from multiple types of injury (2007) Neurochem Res, 32, pp. 321-329 Wang, X., Robinson, P.J., Cyclic GMP-dependent protein kinase and cellular signaling in the nervous system (1997) J Neurochem, 68, pp. 443-456 Abramovitz, M., Adam, M., Boie, Y., Theutilization of recombinant prostanoid receptors to determine the affinities and selectivities of prostaglandins and related analogs (2000) Biochim Biophys Acta, 1483, pp. 285-293 Bilak, M., Wu, L., Wang, Q., Haughey, N., Conant, K., St Hillaire, C., PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis (2004) Ann Neurol, 56, pp. 240-248 Carlson, N.G., Rojas, M.A., Black, J.D., Redd, J.W., Hille, J., Hill, K.E., Microglial inhibition of neuroprotection by antagonists of the EP1 prostaglandin E2 receptor (2009) J Neuroinflammation, 6, p. 5 Farooqui, A.A., Horrocks, L.A., Farooqui, T., Modulation of inflammation in brain: a matter of fat (2007) J Neurochem, 101, pp. 577-599 Dore-Duffy, P., Donaldson, J.O., Koff, T., Longo, M., Perry, W., Prostaglandin release in multiple sclerosis: correlation with disease activity (1986) Neurology, 36, pp. 1587-1590 Neu, I.S., Metzger, G., Zschocke, J., Zelezny, R., Mayatepek, E., Leukotrienes in patients with clinically active multiple sclerosis (2002) Acta Neurol Scand, 105, pp. 63-66 Dore-Duffy, P., Ho, S.Y., Donovan, C., Cerebrospinal fluid eicosanoid levels: endogenous PGD2 and LTC4 synthesis by antigen-presenting cells that migrate to the central nervous system (1991) Neurology, 41, pp. 322-324 Muthian, G., Raikwar, H.P., Johnson, C., Rajasingh, J., Kalgutkar, A., Marnett, L.J., COX-2 inhibitors modulate IL-12 signaling through JAK-STAT pathway leading to Th1 response in experimental allergic encephalomyelitis (2006) J Clin Immunol, 26, pp. 73-85