The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Stefan Endres - One of the best experts on this subject based on the ideXlab platform.
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specific type iv Phosphodiesterase Inhibitor rolipram mitigates experimental colitis in mice
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Gunther Hartmann, Christoph Bidlingmaier, Stefan Albrich, Katharina Tschoep, Hans A Lehr, Britta Siegmund, Johannes Schulze, Andreas Eigler, Stefan EndresAbstract:The specific type IV Phosphodiesterase Inhibitor rolipram is a potent suppressor of tumor necrosis factor-α (TNF) synthesis. We examined the efficacy of rolipram for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulfate sodium in their drinking water continuously for up to 11 days. Colitis was quantified by a clinical activity score assessing weight loss, stool consistency, and rectal bleeding (range from 0 to 4); by colon length; by a semiquantitative histologic score (range from 0 to 6); and by detecting TNF concentration in colonic tissue by enzyme-linked immunosorbent assay. In a first protocol, rolipram (10 mg/kg b.wt./day i.p.) was started on the same day as dextran sulfate sodium. Rolipram reduced the clinical activity of colitis (score 1.1 ± 0.3) compared with mice that did not receive rolipram (2.4 ± 0.4; P = .041). Rolipram also partially reversed the reduction of colon length (without rolipram, 12.4 ± 0.3 cm; with rolipram, 15.4 ± 0.7 cm; P = .004) and improved the histologic score (1.5 ± 0.6 in rolipram-treated mice versus 4.6 ± 0.5; P = .020). Rolipram suppressed colonic tissue TNF concentrations. The beneficial effect of rolipram was confirmed in a second protocol in which dextran sulfate sodium exposure was discontinued on day 7 and rolipram was administered from day 8 through day 15. These three series of experiments on a total of 153 mice documented the efficacy of rolipram in both the prevention and treatment of experimental colitis.
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Rolipram, a specific type IV Phosphodiesterase Inhibitor, is a potent Inhibitor of HIV-1 replication.
AIDS, 1995Co-Authors: Jonathan B. Angel, Bradford M. Saget, Sean P. Walsh, Tim F. Greten, Charles A. Dinarello, Paul R. Skolnik, Stefan EndresAbstract:OBJECTIVE To determine the effects of rolipram, a specific type IV Phosphodiesterase Inhibitor, on tumor necrosis factor (TNF)-alpha production and HIV-1 replication. DESIGN TNF-alpha enhances HIV-1 replication in vitro; blocking TNF-alpha and thereby inhibiting HIV-1 replication may therefore potentially delay progression of HIV disease. Pentoxifylline is a non-specific Phosphodiesterase Inhibitor that blocks TNF-alpha synthesis and HIV-1 replication in vitro and has been shown in preliminary clinical studies to decrease viral replication in HIV-1-infected patients. Rolipram, which selectively inhibits the predominant Phosphodiesterase isoenzyme of monocytes, inhibits lipopolysaccharide (LPS)-induced TNF-alpha with 500-fold greater potency than pentoxifylline. We, therefore, hypothesized that rolipram would be a powerful Inhibitor of HIV-1 replication. METHODS The effects of rolipram and pentoxifylline on TNF-alpha production and HIV-1 replication were determined in infected and uninfected peripheral blood mononuclear cells (PBMC), in a chronically infected promonocytic cell line (U1) and in an acutely infected monocytic cell line (BT4A3.5). TNF-alpha was determined by specific radioimmunoassay and HIV-1 replication was measured by p24 antigen and HIV-1 mRNA production. RESULTS Rolipram inhibited TNF-alpha production in LPS- and phorbol myristate acetate (PMA)-stimulated PBMC and in PMA-stimulated U1 cells. Rolipram also inhibited HIV-1 replication in the U1 cell line, as well as in acutely infected PBMC and BT4A3.5 cells. Depending on the experimental conditions, rolipram was 10-600 times more potent, on a molar basis, than pentoxifylline. CONCLUSION Rolipram is a potent Inhibitor HIV-1 replication and therefore deserves further investigation as a potential therapeutic agent in the treatment of HIV-1-infected patients.
Eric R Kandel - One of the best experts on this subject based on the ideXlab platform.
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rolipram a type iv specific Phosphodiesterase Inhibitor facilitates the establishment of long lasting long term potentiation and improves memory
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Mark Barad, Roussoudan Bourtchouladze, Danny G Winder, Hava Golan, Eric R KandelAbstract:In an attempt to improve behavioral memory, we devised a strategy to amplify the signal-to-noise ratio of the cAMP pathway, which plays a central role in hippocampal synaptic plasticity and behavioral memory. Multiple high-frequency trains of electrical stimulation induce long-lasting long-term potentiation, a form of synaptic strengthening in hippocampus that is greater in both magnitude and persistence than the short-lasting long-term potentiation generated by a single tetanic train. Studies using pharmacological Inhibitors and genetic manipulations have shown that this difference in response depends on the activity of cAMP-dependent protein kinase A. Genetic studies have also indicated that protein kinase A and one of its target transcription factors, cAMP response element binding protein, are important in memory in vivo. These findings suggested that amplification of signals through the cAMP pathway might lower the threshold for generating long-lasting long-term potentiation and increase behavioral memory. We therefore examined the biochemical, physiological, and behavioral effects in mice of partial inhibition of a hippocampal cAMP Phosphodiesterase. Concentrations of a type IV-specific Phosphodiesterase Inhibitor, rolipram, which had no significant effect on basal cAMP concentration, increased the cAMP response of hippocampal slices to stimulation with forskolin and induced persistent long-term potentiation in CA1 after a single tetanic train. In both young and aged mice, rolipram treatment before training increased long- but not short-term retention in freezing to context, a hippocampus-dependent memory task.
Julietta Uta Frey - One of the best experts on this subject based on the ideXlab platform.
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the type iv specific Phosphodiesterase Inhibitor rolipram and its effect on hippocampal long term potentiation and synaptic tagging
The Journal of Neuroscience, 2004Co-Authors: Sheeja Navakkode, Sreedharan Sajikumar, Julietta Uta FreyAbstract:We investigated the effects of rolipram, a selective cAMP Phosphodiesterase (PDE) Inhibitor, on late plastic events during functional CA1 plasticity in vitro in rat hippocampal slices. We present data showing that an early form of long-term potentiation (LTP) (early-LTP) that normally decays within 2-3 hr can be converted to a lasting LTP (late-LTP) if rolipram is applied during tetanization. This rolipram-reinforced LTP (RLTP) was NMDA receptor and protein synthesis dependent. cAMP formation in region CA1 during late-LTP requires dopaminergic receptor activity ([Frey et al., 1989][1], [1990][2]). Thus, we studied whether RLTP was influenced by Inhibitors of the D1/D5 receptor. Application of the specific D1/D5 antagonist [SCH23390][3] (0.1 μm) did not prevent RLTP, suggesting that the Phosphodiesterase Inhibitor acts downstream of the D1/D5 receptors. We also studied whether rolipram can interact with processes of synaptic tagging, because RLTP was also dependent on protein synthesis, similar to late-LTP. Inhibition of PDE and subsequent induction of RLTP in one synaptic population were able to transform early-LTP into late-LTP in a second, independent synaptic population of the same neurons. This supports our hypothesis that cAMP-dependent processes are directly involved in the synthesis of plasticity-related proteins. [1]: #ref-16 [2]: #ref-17 [3]: /lookup/external-ref?link_type=GENPEPT&access_num=SCH23390&atom=%2Fjneuro%2F24%2F35%2F7740.atom
Ethan S. Weiner - One of the best experts on this subject based on the ideXlab platform.
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Type 4 Phosphodiesterase Inhibitors Have Clinical and In Vitro Anti-inflammatory Effects in Atopic Dermatitis
The Journal of investigative dermatology, 1996Co-Authors: Jon M. Hanifin, Sai C. Chan, John B. Cheng, Susan J. Tofte, William R. Henderson, Deborah S. Kirby, Ethan S. WeinerAbstract:Increased cyclic AMP-Phosphodiesterase activity in peripheral blood leukocytes is associated with the immune and inflammatory hyperreactivity that characterizes atopic dermatitis. Atopic Phosphodiesterase has high sensitivity to a variety of enzyme Inhibitors, suggesting an increased therapeutic advantage. The objective of this study was to use in vitro assays to identify a potent Phosphodiesterase Inhibitor and then to investigate its effectiveness in treating atopic dermatitis. Leukocyte enzyme activity was measured by radioenzyme assay, whereas prostaglandin E 2 and interleukins 10 (IL-10) and 4 (IL-4) were measured in 24-h culture supernatants of mononuclear leukocytes by immunoassays. The effect of a topical Phosphodiesterase Inhibitor on atopic dermatitis lesional skin was assessed by double-blind, paired comparisons of active drug and placebo ointments applied to symmetrically involved sites over a 28-d period. Using in vitro assays, we demonstrated the ability of selective high-potency Phosphodiesterase Inhibitors to reduce prostaglandin E 2 , IL-10, and IL-4 production in atopic mononuclear leukocyte cultures. We selected the Type 4 Phosphodiesterase Inhibitor, CP80,633, based on its Inhibitory potency, for clinical testing by topical, bilateral paired comparisons in 20 patients with atopic dermatitis and demonstrated significant reductions of all inflammatory parameters. Phosphodiesterase Inhibitors modulate several pathways contributing to the exaggerated immune and inflammatory responses, which characterize atopic dermatitis. This in vivo demonstration of anti-inflammatory efficacy may provide a useful alternative to the over-reliance on corticosteroid therapy in atopic disease.
William D Steers - One of the best experts on this subject based on the ideXlab platform.
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sildenafil a type 5 cgmp Phosphodiesterase Inhibitor specifically amplifies endogenous cgmp dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro
The Journal of Urology, 1998Co-Authors: Alex T Chuang, John D Strauss, Richard A Murphy, William D SteersAbstract:AbstractPurpose: The primary mechanism for relaxation of corpus cavernosum smooth muscle (CCSM) and penile erection depends upon nitric oxide (NO)-induced elevation of myoplasmic cyclic guanosine monophosphate (cGMP). Agents that enhance the NO-cGMP signal transduction pathway may prove beneficial in treating erectile dysfunction. Sildenafil, a selective type-5 cGMP Phosphodiesterase Inhibitor, was investigated to determine the specific mechanism(s) involved in the therapeutic use of this compound to treat impotence.Materials and Methods: Isolated strips of rabbit corpus cavernosum were stimulated isometrically with phenylephrine. Graded relaxations were induced using various concentrations of sodium nitroprusside (SNP) alone and in combination with sildenafil. At fixed times, the tissues were rapidly frozen and processed for myosin light chain (MLC) phosphorylation using isoelectric focusing with Western blot analysis, and cGMP content using radioimmunoassay techniques.Results: Sildenafil alone reduced s...