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The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis

Nature Medicine volume 1, pages 244–248 (1995)Cite this article

Abstract

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) the cytokines tumour necrosis factor-α (TNF), lymphotoxin-α (LT), and interferon-gamma (IFN-γ) are of central pathogenetic importance. A therapy capable of stopping neurological deterioration in MS patients is not yet available. Here, we report that rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/LT and less strongly also IFN-γ in human and rat auto-reactive T cells. Moreover, we show that rolipram is an effective treatment for EAE. Rolipram has extensively been studied in humans for the treatment of depression, but has not yet been marketed. The data presented here identify rolipram as potential therapy for multiple sclerosis and provoke the immediate initiation of clinical trials.

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References

  1. Martin, R., McFarland, H.F. & McFarlin, D. Immunological aspects of demyelinating diseases. Annu. Rev. Immunol. 10, 153–187 (1992).

    Article  CAS  Google Scholar 

  2. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43, 655–661 (1993).

  3. Selmaj, K., Raine, C.S., Canella, B. & Brosnan, C.F. Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J. clin. Invest. 87, 949–954 (1991).

    Article  CAS  Google Scholar 

  4. Selmaj, K. & Raine, C.S. Tumor necrosis factor mediates myelin and oligo-dendrocyte damage in vitro . Ann. Neurol. 23, 339–346 (1988).

    Article  CAS  Google Scholar 

  5. Powell, M.B. et al. Lymphotoxin and tumor necrosis factor-alpha production by myelin basic protein-specific T cell clones correlates with encephalitogenicity. Int. Immun. 2, 539–544 (1990).

    Article  CAS  Google Scholar 

  6. Kuchroo, V.K. et al. Cytokines and adhesion molecules contribute to the ability of myelin proteolipid protein-specific T-cell clones to mediate experimental allergic encephalomyelitis. J. Immun. 151, 4371–4382 (1993).

    CAS  PubMed  Google Scholar 

  7. Chung, I.Y., Norris, J.G. & Benveniste, E.N. Differential tumor necrosis factor alpha expression by astrocytes from experimental allergic encephalomyelitis-susceptible and-resistant rat strains. J. exp. Med. 173, 801–811 (1991).

    Article  CAS  Google Scholar 

  8. Ruddle, N.H. et al. An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J. exp. Med. 172, 1193–1200 (1990).

    Article  CAS  Google Scholar 

  9. Panitch, H.S., Hirsch, R.L., Haley, A.S. & Johnson, K.P. Exacerbations of multiple sclerosis in patients treated with gamma interferon. Lancet 1, 893–895 (1987).

    Article  CAS  Google Scholar 

  10. Davis, C.W. Assessment of selective inhibition of rat cerebral cortical calcium-dependent phosphodiesterases in crude extracts using deoxycyclic AMP and potassium ions. Biochim. biophys. Acta 797, 354–362 (1984).

    Article  CAS  Google Scholar 

  11. Wachtel, H. & Schneider, H.H., Rolipram, a novel antidepressant drug, reverses the hypothermia and hypokinesia of monoamine-depleted mice by an action beyond postsynaptic monoamine receptors. Neuropharmacology 25, 1119–1126 (1986).

    Article  CAS  Google Scholar 

  12. Scott, A.I.F., Perini, A.F., Shering, P.A. & Whalley, L.J. In-patient major depression: Is rolipram as effective as amitriptyline? Eur. J. clin. Pharmac. 40, 127–129 (1991).

    Article  CAS  Google Scholar 

  13. Suttorp, N., Weber, U., Welsch, T. & Schudt, C. Role of phosphodiesterases in the regulation of endothelial permeability in vitro . J. clin. Invest. 91, 1421–1428 (1993).

    Article  CAS  Google Scholar 

  14. Semmler, J., Wachtel, H. & Endres, S. The specific type IV phosphodiesterase inhibitor rolipram suppresses tumor necrosis factor-alpha production by human mononuclear cells. Int. J. Immunopharmac. 15, 409–413 (1993).

    Article  CAS  Google Scholar 

  15. Beavo, J.A. & Reifsnyder, D.H. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends pharmac. Sci. 11, 150–155 (1990).

    Article  CAS  Google Scholar 

  16. McLaughlin, M.M., Cieslinski, L.B., Burman, M., Torphy, T.J. & Livi, G.P. A low-Km, rolipram-sensitive, cAMP-specific phosphodiesterase from human brain. J. biol. Chem. 268, 6470–6476 (1993).

    CAS  PubMed  Google Scholar 

  17. Ichimura, M. & Kase, H. A new cyclic nucleotide phosphodiesterase isozyme expressed in the T-lymphocyte cell lines. Biochem. biophys. Res. Commun. 193, 985–990 (1993).

    Article  CAS  Google Scholar 

  18. Martin, R. et al. Diversity in fine specificity and T cell receptor usage of the human CD4+ cytotoxic T cell response specific for the immunodominant myelin basic protein peptide 87–106. J. Immun. 148, 1359–1366 (1992).

    CAS  PubMed  Google Scholar 

  19. Schmiechen, R., Schneider, H.H. & Wachtel, H. Close correlation between behavioural response and binding in vivo for inhibitors of the rolipram-sensitive phosphodiesterase. Psychopharmacology 102, 17–20 (1990).

    Article  CAS  Google Scholar 

  20. Kaulen, P., Brüning, G., Schneider, H.H., Sarter, M. & Baumgarten, H.G. Autoradiographic mapping of a selective cyclic adenosine monophosphate phosphodiesterase in rat brain with the antidepressant [3H]rolipram. Brain Res. 503, 229–245 (1989).

    Article  CAS  Google Scholar 

  21. Linington, C. et al. T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. Eur. J. Immun. 23, 1364–1372 (1993).

    Article  CAS  Google Scholar 

  22. Spengler, R.N. et al. Dynamics of dibutyryl cyclic AMP-and prostaglandin E2-mediated suppression of lipopolysaccharide-induced tumor necrosis factor alpha gene expression. Infect. Immun. 57, 2837–2841 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Phipps, R.P., Stein, S.H. & Roper, R.L. A new view of prostaglandin E regulation of the immune response. Immun. Today 12, 349–352 (1991).

    Article  CAS  Google Scholar 

  24. Racke, M.K. et al. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J. exp. Med. 180, 1961–1966 (1994).

    Article  CAS  Google Scholar 

  25. Racke, M.K. et al. Evidence for endogenous regulatory function of transforming growth factor-β 1 in experimental allergic encephalomyelitis. Int. Immun. 4, 615–620 (1992).

    Article  CAS  Google Scholar 

  26. Herve, P. et al. Phase I-II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease. Blood 79, 3362–3368 (1992).

    Article  CAS  Google Scholar 

  27. Lindsey, J.W. et al. Repeated treatment with chimeric anti-CD4 antibody in multiple sclerosis. Ann. Neural. 36, 183–189 (1994).

    Article  CAS  Google Scholar 

  28. Krause, W., Kuhne, G. & Matthes, H. Pharmacokinetics of the antidepressant rolipram in healthy volunteers. Xenobiotica 19, 683–692 (1989).

    Article  CAS  Google Scholar 

  29. Fleischhacker, W.W. et al. A multicenter double-blind study of three different doses of the new cAMP-phosphodiesterase inhibitor rolipram in patients with major depressive disorders. Neuropsychobiology 26, 59–64 (1992).

    Article  CAS  Google Scholar 

  30. Hebenstreit, G.F. et al. Rolipram in major depressive disorder: Results of a double-blind comparative study with imipramine. Pharmacopsychiatry 22, 156–160 (1989).

    Article  CAS  Google Scholar 

  31. Dezube, B.J. et al. Pentoxifylline decreases tumor necrosis factor expression and serum triglycerides in people with AIDS. NIAID AIDS clinical trial group. J. Acquir. Immune Deflc. Syndr. 6, 787–794 (1993).

    CAS  Google Scholar 

  32. Stoll, G., Jung, S., Jander, S., van der Meide, P., Hartung, H.P. Tumor necrosis factor-alpha in immune-mediated demyelination and Wallerian degeneration of the rat peripheral nervous system. J. Neuroimmun. 45, 175–182 (1993).

    Article  CAS  Google Scholar 

  33. Ben-Nun, A., Wekerle, H., Cohen, I.R. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur. J. Immun. 11, 195–199 (1981).

    Article  CAS  Google Scholar 

  34. Frei, K. et al. Antigen presentation and tumor cytotoxicity by interferon-gamma-treated microgial cells. Eur. J. Immun. 17, 1271–1278 (1987).

    Article  CAS  Google Scholar 

  35. Swanborg, R.H. Experimental allergic encephalomyelitis. Methods Enzymol. 162, 413–421 (1988).

    Article  CAS  Google Scholar 

  36. Umehara, F., Qin, Y., Wekerle, H., Meyermann, R. Experimental autoimmune encephalomyelitis in the maturing central nervous system. Lab. Invest. 62, 147–155 (1990).

    CAS  PubMed  Google Scholar 

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Author notes

  1. N. Sommer: Correspondence should be addressed to N.S.

Authors and Affiliations

  1. Department of Neurology, Tübingen University, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany

    N. Sommer, P.-A. Löschmann, A. Steinbrecher, J.P. Steinbach, R. Lichtenfels, A. Riethmüller, J. Dichgans & R. Martin

  2. Department of Transfusion Medicine, Tübingen University, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany

    G.H. Northoff

  3. Section of Clinical Immunology, Department of Internal Medicine, University Hospital, Mousson-Str. 13, 8044, Zurich, Switzerland

    M. Weller & A. Fontana

  4. Institute for Brain Research, Tübin;gen University, Calwer-Str. 3, 72076, Tübingen, Germany

    R. Meyermann

  5. Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    R. Martin

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Sommer, N., Löschmann, PA., Northoff, G. et al. The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med 1, 244–248 (1995). https://doi.org/10.1038/nm0395-244

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