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Chemical Compound Review

rolipram     4-(3-cyclopentyloxy-4- methoxy...

Synonyms: Rolipramum, Adeo, CHEMBL63, UPCMLD-DP110, SureCN27930, ...
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Disease relevance of rolipram

  • The data presented here identify rolipram as potential therapy for multiple sclerosis and provoke the immediate initiation of clinical trials [1].
  • The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis [1].
  • We thus explored whether administration in vivo of the selective PDE-III antagonist, lixazinone (LX), together with the specific PDE-IV antagonist, rolipram (RP), can attenuate development of mesangioproliferative glomerulonephritis (MSGN) induced in rats by anti-rat thymocyte serum (ATS) [2].
  • Unlike the vehicle-treated MSGN rats, rats with MSGN treated with LX and RP did not develop proteinuria and maintained normal renal function when examined 5 d after injection of ATS [2].
  • Such hyperactivation was accomplished by recruiting the rolipram-sensitive cyclic nucleoside phosphodiesterase 4 and resulted in increased susceptibility to HIV-1 infection [3].

Psychiatry related information on rolipram


High impact information on rolipram

  • Inhibition of cAMP hydrolysis by the phosphodiesterase IV inhibitor rolipram prevents this decrease and when combined with Schwann cell grafts promotes significant supraspinal and proprioceptive axon sparing and myelination [8].
  • Here, we report that rolipram, a selective type IV phosphodiesterase inhibitor, stereospecifically suppresses the production of TNF/LT and less strongly also IFN-gamma in human and rat auto-reactive T cells [1].
  • Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice [4].
  • Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates [9].
  • The phosphodiesterase (PDE) inhibitors motapizone (10(-4) M), rolipram (10(-6) M), and zardaverine (10(-8) M), which specifically inhibit PDE-isoenzymes III, IV, and III/IV potently blocked H2O2-induced endothelial permeability when combined with 10(-6) M prostaglandin E1 [10].

Chemical compound and disease context of rolipram


Biological context of rolipram

  • The PKA phosphorylation status of the beta(2)AR is enhanced markedly when cells are treated with the selective PDE4-inhibitor rolipram or when they are transfected with a catalytically inactive PDE4D mutant (PDE4D5-D556A) that competitively inhibits isoprenaline-stimulated recruitment of native PDE4 to the beta(2)AR [16].
  • Rolipram/forskolin treatment augmented protein phosphatase 2A (PP2A) activity, as well as levels of immunoreactive PP2A catalytic subunit [11].
  • In samples from 13 of 14 CLL patients, rolipram induced apoptosis in a dose-dependent fashion over a 48-hour period [17].
  • Consistent with these findings, we show that pharmacologic elevation of cAMP with the phosphodiesterase inhibitor Rolipram suppresses tumor cell growth in vitro and, upon oral administration, inhibits intracranial growth in xenograft models of malignant brain tumors with comparable efficacy to AMD 3465 [18].
  • In addition to inhibiting the catalytic activity of PDE IV, rolipram binds to a high affinity binding site present in brain homogenates [19].

Anatomical context of rolipram

  • The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery [20].
  • Antisense depletion of murine PDE4A5 mimicked the ability of rolipram to enhance the growth hormone-stimulated differentiation of 3T3-F442A cells to adipocytes [21].
  • We now show that the phosphodiesterase 4 (PDE4) inhibitor rolipram (which readily crosses the blood-brain barrier) overcomes inhibitors of regeneration in myelin in culture and promotes regeneration in vivo [20].
  • Sensitivity to forskolin and rolipram is shared by at least 2 pediatric ALL cell lines, CEM and Reh cells [22].
  • Interleukin-2 (IL-2)-cultured whole mononuclear cells (WMC) and anti-Ig stimulated CD19(+) B cells were resistant to the induction of apoptosis by rolipram while unstimulated CD19(+) B cells, which had a high basal apoptotic rate, were more sensitive [17].

Associations of rolipram with other chemical compounds

  • We show that treatment of CLL cells with rolipram, a prototypic PDE4 inhibitor, and forskolin, an adenylate cyclase activator, induces mitochondrial depolarization, release of cytochrome c into the cytosol, caspase-9 and -3 activation, and cleavage of poly(adenosine diphosphate [ADP]-ribose)polymerase [11].
  • The excitatory effects of intrathecally infused dibutyryl cAMP, 8-bromo cAMP, forskolin-DHA, or Rolipram support a functional link between spinal cord cAMP and the acoustic startle reflex [23].
  • Transfection of COS7 cells with a plasmid encoding the human cyclic AMP-specific PDE4A phosphodiesterase PDE-46 (HSPDE4A4B) led to the expression of a rolipram-inhibited PDE4 activity, which contributed approximately 96% of the total COS cell PDE activity [24].
  • Selective PDE IV inhibitors (rolipram and RO-20-1724), but not selective inhibitors of other types of PDE, significantly augment marcrophage IL-10 production and contribute to the inhibition of TNF-alpha and IL-6 release [25].
  • Conversely, cilostamide or lixazinone suppressed mitogenic synthesis of DNA in mesangial cells, but 1 microM rolipram or 1 microM denbufylline showed no inhibitory effect [26].

Gene context of rolipram

  • Accordingly, rolipram potently inhibited HIV-1 replication in cultures stimulated by anti-CD3/CD28 +/- Tat [3].
  • Pretreatment with anti-TNF-alpha monoclonal antibody (25 mg/kg IV, n = 7) or the TNF-alpha synthesis inhibitor rolipram (200 micrograms/kg IV, n = 7) attenuated lung injury and reverted tissue hypoxia [27].
  • Such an interaction profoundly changed the inhibition of PDE4 activity caused by the PDE4-selective inhibitor rolipram and mimicked the enhanced rolipram inhibition seen for particulate, compared with cytosolic pde46 expressed in COS7 cells [28].
  • Association with the SRC family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B. Consequences for rolipram inhibition [28].
  • The selective PDE4 inhibitor rolipram increases AKAP-tethered PKA activity on AQP2-bearing vesicles and enhances the AQP2 shuttle and thereby the osmotic water permeability [29].

Analytical, diagnostic and therapeutic context of rolipram


  1. The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Sommer, N., Löschmann, P.A., Northoff, G.H., Weller, M., Steinbrecher, A., Steinbach, J.P., Lichtenfels, R., Meyermann, R., Riethmüller, A., Fontana, A. Nat. Med. (1995) [Pubmed]
  2. Suppression of mesangial proliferative glomerulonephritis development in rats by inhibitors of cAMP phosphodiesterase isozymes types III and IV. Tsuboi, Y., Shankland, S.J., Grande, J.P., Walker, H.J., Johnson, R.J., Dousa, T.P. J. Clin. Invest. (1996) [Pubmed]
  3. Pivotal role of cyclic nucleoside phosphodiesterase 4 in Tat-mediated CD4+ T cell hyperactivation and HIV type 1 replication. Secchiero, P., Zella, D., Curreli, S., Mirandola, P., Capitani, S., Gallo, R.C., Zauli, G. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  4. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. Gong, B., Vitolo, O.V., Trinchese, F., Liu, S., Shelanski, M., Arancio, O. J. Clin. Invest. (2004) [Pubmed]
  5. The effects of a selective cAMP phosphodiesterase inhibitor, rolipram, on methamphetamine-induced behavior. Iyo, M., Maeda, Y., Inada, T., Kitao, Y., Sasaki, H., Fukui, S. Neuropsychopharmacology (1995) [Pubmed]
  6. Involvement of cyclic AMP systems in morphine physical dependence in mice: prevention of development of morphine dependence by rolipram, a phosphodiesterase 4 inhibitor. Mamiya, T., Noda, Y., Ren, X., Hamdy, M., Furukawa, S., Kameyama, T., Yamada, K., Nabeshima, T. Br. J. Pharmacol. (2001) [Pubmed]
  7. Potential antidepressant activity of rolipram and other selective cyclic adenosine 3',5'-monophosphate phosphodiesterase inhibitors. Wachtel, H. Neuropharmacology (1983) [Pubmed]
  8. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury. Pearse, D.D., Pereira, F.C., Marcillo, A.E., Bates, M.L., Berrocal, Y.A., Filbin, M.T., Bunge, M.B. Nat. Med. (2004) [Pubmed]
  9. Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. Robichaud, A., Stamatiou, P.B., Jin, S.L., Lachance, N., MacDonald, D., Laliberté, F., Liu, S., Huang, Z., Conti, M., Chan, C.C. J. Clin. Invest. (2002) [Pubmed]
  10. Role of phosphodiesterases in the regulation of endothelial permeability in vitro. Suttorp, N., Weber, U., Welsch, T., Schudt, C. J. Clin. Invest. (1993) [Pubmed]
  11. PDE4 inhibitors activate a mitochondrial apoptotic pathway in chronic lymphocytic leukemia cells that is regulated by protein phosphatase 2A. Moon, E.Y., Lerner, A. Blood (2003) [Pubmed]
  12. Opposing roles of cyclic AMP in the vascular control of edema formation. Warren, J.B., Wilson, A.J., Loi, R.K., Coughlan, M.L. FASEB J. (1993) [Pubmed]
  13. Dextran sulfate sodium-induced colonic histopathology, but not altered epithelial ion transport, is reduced by inhibition of phosphodiesterase activity. Diaz-Granados, N., Howe, K., Lu, J., McKay, D.M. Am. J. Pathol. (2000) [Pubmed]
  14. Maintenance of cAMP in non-heart-beating donor lungs reduces ischemia-reperfusion injury. Hoffmann, S.C., Bleiweis, M.S., Jones, D.R., Paik, H.C., Ciriaco, P., Egan, T.M. Am. J. Respir. Crit. Care Med. (2001) [Pubmed]
  15. Inhibition of phosphodiesterase type IV suppresses human immunodeficiency virus type 1 replication and cytokine production in primary T cells: involvement of NF-kappaB and NFAT. Navarro, J., Punzón, C., Jiménez, J.L., Fernández-Cruz, E., Pizarro, A., Fresno, M., Muñoz-Fernández, M.A. J. Virol. (1998) [Pubmed]
  16. beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Baillie, G.S., Sood, A., McPhee, I., Gall, I., Perry, S.J., Lefkowitz, R.J., Houslay, M.D. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  17. Type 4 cyclic adenosine monophosphate phosphodiesterase as a therapeutic target in chronic lymphocytic leukemia. Kim, D.H., Lerner, A. Blood (1998) [Pubmed]
  18. Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Yang, L., Jackson, E., Woerner, B.M., Perry, A., Piwnica-Worms, D., Rubin, J.B. Cancer Res. (2007) [Pubmed]
  19. Coexpression of human cAMP-specific phosphodiesterase activity and high affinity rolipram binding in yeast. Torphy, T.J., Stadel, J.M., Burman, M., Cieslinski, L.B., McLaughlin, M.M., White, J.R., Livi, G.P. J. Biol. Chem. (1992) [Pubmed]
  20. The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Nikulina, E., Tidwell, J.L., Dai, H.N., Bregman, B.S., Filbin, M.T. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  21. Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes. MacKenzie, S.J., Yarwood, S.J., Peden, A.H., Bolger, G.B., Vernon, R.G., Houslay, M.D. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  22. Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells. Ogawa, R., Streiff, M.B., Bugayenko, A., Kato, G.J. Blood (2002) [Pubmed]
  23. The role of spinal cord cyclic AMP in the acoustic startle response in rats. Kehne, J.H., Astrachan, D.I., Astrachan, E., Tallman, J.F., Davis, M. J. Neurosci. (1986) [Pubmed]
  24. The human cyclic AMP-specific phosphodiesterase PDE-46 (HSPDE4A4B) expressed in transfected COS7 cells occurs as both particulate and cytosolic species that exhibit distinct kinetics of inhibition by the antidepressant rolipram. Huston, E., Pooley, L., Julien, P., Scotland, G., McPhee, I., Sullivan, M., Bolger, G., Houslay, M.D. J. Biol. Chem. (1996) [Pubmed]
  25. Cyclic nucleotide phosphodiesterase type IV participates in the regulation of IL-10 and in the subsequent inhibition of TNF-alpha and IL-6 release by endotoxin-stimulated macrophages. Kambayashi, T., Jacob, C.O., Zhou, D., Mazurek, N., Fong, M., Strassmann, G. J. Immunol. (1995) [Pubmed]
  26. Compartmentalization of cAMP signaling in mesangial cells by phosphodiesterase isozymes PDE3 and PDE4. Regulation of superoxidation and mitogenesis. Chini, C.C., Grande, J.P., Chini, E.N., Dousa, T.P. J. Biol. Chem. (1997) [Pubmed]
  27. Locally produced tumor necrosis factor-alpha mediates interleukin-2-induced lung injury. Rabinovici, R., Feuerstein, G., Abdullah, F., Whiteford, M., Borboroglu, P., Sheikh, E., Phillip, D.R., Ovadia, P., Bobroski, L., Bagasra, O., Neville, L.F. Circ. Res. (1996) [Pubmed]
  28. Association with the SRC family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B. Consequences for rolipram inhibition. McPhee, I., Yarwood, S.J., Scotland, G., Huston, E., Beard, M.B., Ross, A.H., Houslay, E.S., Houslay, M.D. J. Biol. Chem. (1999) [Pubmed]
  29. Compartmentalization of cAMP-Dependent Signaling by Phosphodiesterase-4D Is Involved in the Regulation of Vasopressin-Mediated Water Reabsorption in Renal Principal Cells. Stefan, E., Wiesner, B., Baillie, G.S., Mollajew, R., Henn, V., Lorenz, D., Furkert, J., Santamaria, K., Nedvetsky, P., Hundsrucker, C., Beyermann, M., Krause, E., Pohl, P., Gall, I., Macintyre, A.N., Bachmann, S., Houslay, M.D., Rosenthal, W., Klussmann, E. J. Am. Soc. Nephrol. (2007) [Pubmed]
  30. Suppression of TNF-alpha expression, inhibition of Th1 activity, and amelioration of collagen-induced arthritis by rolipram. Ross, S.E., Williams, R.O., Mason, L.J., Mauri, C., Marinova-Mutafchieva, L., Malfait, A.M., Maini, R.N., Feldmann, M. J. Immunol. (1997) [Pubmed]
  31. The short-term activation of a rolipram-sensitive, cAMP-specific phosphodiesterase by thyroid-stimulating hormone in thyroid FRTL-5 cells is mediated by a cAMP-dependent phosphorylation. Sette, C., Iona, S., Conti, M. J. Biol. Chem. (1994) [Pubmed]
  32. Effects of rolipram on responses to acute and chronic antigen exposure in monkeys. Turner, C.R., Andresen, C.J., Smith, W.B., Watson, J.W. Am. J. Respir. Crit. Care Med. (1994) [Pubmed]
  33. Differential efficacy of lymphocyte- and monocyte-selective pretreatment with a type 4 phosphodiesterase inhibitor on antigen-driven proliferation and cytokine gene expression. Essayan, D.M., Huang, S.K., Kagey-Sobotka, A., Lichtenstein, L.M. J. Allergy Clin. Immunol. (1997) [Pubmed]
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