Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

First-generation phosphodiesterase 4 (PDE4) inhibitors, such as rolipram, inhibit the activation of immune and inflammatory cells. The clinical use of these compounds is limited by gastrointestinal side effects, such as increased acid secretion and nausea. Consequently, the challenge has been to design novel PDE4 inhibitors that maintain the anti-inflammatory actions of rolipram while achieving an improved side effect profile. Among the first of this new class of PDE4 inhibitors specifically designed to have an improved therapeutic index relative to earlier compounds is SB 207499 (Ariflo) [c-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-r-1-cyclohexanecarboxyl ic acid]. In this study, we compared the anti-inflammatory and gastric secretogogue activities of SB 207499 with those of rolipram. The cellular models used were (1) histamine release from human basophils, (2) tumor necrosis factor-alpha generation in human monocytes, (3) degranulation of human neutrophils, (4) antigen-driven proliferation and cytokine synthesis from human T cells and (5) acid secretion from isolated rabbit gastric glands. SB 207499 inhibited the activation of a variety of immune and inflammatory cells in a concentration-dependent manner: (1) histamine release in basophils [-log IC25 = 6.6 +/- 0.3 vs. 8.0 for (R)-rolipram], (2) lipopolysacchride-induced TNF-alpha formation in monocytes [-log IC50 = 7.0 +/- 0.1 vs. 7.2 +/- 0.1 for (R)-rolipram], (3) fMLP-induced degranulation in neutrophils [-log IC15 = 7.1 +/- 0.2 vs. 6.4 +/- 0.5 for (R)-rolipram], (4) house dust mite induced-proliferation of peripheral blood mononuclear cells [-log IC40 = 6.5 +/- 0.3 vs. 6.4 +/- 0.3 for (R)-rolipram] and (5) ragweed-induced production of interferon-gamma [-log IC50 = 5.4] and interleukin-5 [-log IC50 = 5.0]. Although SB 207499 inhibits the activation of a variety of immune and inflammatory cells with a potency equal to that of rolipram, it is > 100-fold less potent than the latter compound as an acid secretagogue [-log EC50 = 6.1 +/- 0.1 vs. 8.3 +/- 0.2 for (R)-rolipram]. Collectively, these data indicate that SB 207499 retains the anti-inflammatory activity of the prototypical PDE4 inhibitor rolipram but is substantially less likely to stimulate gastric acid secretion.
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PMID:SB 207499 (Ariflo), a potent and selective second-generation phosphodiesterase 4 inhibitor: in vitro anti-inflammatory actions. 943 6

Cytokine-stimulated astrocytes and macrophages are potent producers of nitric oxide (NO), a free radical proposed to play an important role in organ-specific autoimmunity, including demyelinating diseases of the central nervous system. The aim of this study was to investigate effects of pentoxifylline (PTX), a phosphodiesterase inhibitor with immunomodulatory properties, on NO production and inducible NO synthase (iNOS) mRNA expression in rat astrocytes and macrophages. We have shown that PTX affects cytokine (interferon-gamma, IFN-gamma; interleukin-1, IL-1; tumour-necrosis factor-alpha, TNF-alpha)-induced NO production in both cell types, but in the opposite manner--enhancing in astrocytes and suppressive in macrophages. While PTX did not have any effect on enzymatic activity of iNOS in activated cells, expression of iNOS mRNA was elevated in astrocytes and decreased in macrophages treated with cytokines and PTX. Treatment with PTX alone affected neither NO production nor iNOS mRNA levels in astrocytes or macrophages. This study indicates involvement of different signalling pathways associated with iNOS induction in astrocytes and macrophages, thus emphasizing complexity of regulation of NO synthesis in different cell types.
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PMID:Cell-specific effects of pentoxifylline on nitric oxide production and inducible nitric oxide synthase mRNA expression. 948 15

Subcutaneous application of interferon-beta1b (IFN-beta1b) is an established therapy for patients with relapsing-remitting multiple sclerosis (RRMS), but early side effects are still a major concern. In vitro studies with myelin basic protein (MBP)-specific T-cell lines revealed a synergistic suppressive effect of IFN-beta1b and the phosphodiesterase inhibitor pentoxifylline (PTX) on proliferation and the production of tumor necrosis factor-alpha (TNF-alpha), lymphotoxin (LT), and interferon-gamma (IFN-gamma). In an initial, open labeled prospective trial, the cytokine messenger RNA (mRNA) expression of blood mononuclear cells from MS patients, receiving either IFN-beta1b alone or in combination with oral PTX, was determined by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Patients treated with IFN-beta1b alone reported more side effects during the first 3 months of treatment and had upregulated TNF-alpha as well as IFN-gamma mRNA expression during the first month, which was not detected in patients receiving both drugs. A synergistic effect of both drugs was observed on the upregulation of interleukin (IL)-10 mRNA, which was accompanied by an increase in IL-10 serum levels. Both in vitro and in vivo data suggest that co-treatment of IFN-beta1b with PTX is a promising approach to correct the disturbed cytokine balance in MS patients.
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PMID:Synergistic immunomodulatory effects of interferon-beta1b and the phosphodiesterase inhibitor pentoxifylline in patients with relapsing-remitting multiple sclerosis. 966 87

While a differential sensitivity to cyclic AMP (cAMP)-mediated signaling between Th1 and Th2 cells has been hypothesized, differential activity of downstream signaling through cAMP-dependent protein kinase (cAK) isoforms remains unexplored. We herein report the effects of type 1- and type 2-specific cAK agonists and antagonists on proliferative responses and cytokine generation from ragweed-driven peripheral blood mononuclear cells (PBMCs) and Amb a 1-specific Th1 and Th2 clones. Rp-8-Cl- and Rp-8-CPT-cAMP were utilized as single agent antagonists of cAKI and cAKII, respectively; 8-AHA-cAMP, with and without 8-PIP-cAMP, and 8-CPT-cAMP, with and without 6-Bnz-cAMP, were used as synergistic agonist pairs specific for the cAKI and cAKII, respectively. Activation of either cAKI or cAKII individually was ineffective in down-regulating proliferative responses of PBMCs or T cell clones; concentration-response curves for the Th1 and Th2 clones were identical. Moreover, inhibition of either cAKI or cAKII individually was ineffective in overcoming the down-regulatory effects of phosphodiesterase inhibition. Activation of either cAKI or cAKII individually was ineffective in down-regulating proinflammatory cytokine generation from T cell clones (interleukin-4 from Th2; interferon-gamma from Th1). However, concurrent activation of both cAKI and cAKII produced down-regulatory effects equivalent to those of the phosphodiesterase inhibitor on both proliferation and cytokine generation. These data suggest a critical role for concurrent activation of cAKI and cAKII in the functional efficacy of antigen-driven downstream signaling due to elevations of intracellular cAMP and argue against differential regulation of Th1 and Th2 responses by cAK subtypes.
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PMID:Co-regulation of antigen-specific T lymphocyte responses by type I and type II cyclic AMP-dependent protein kinases (cAK). 977 49

Rolipram is a type IV phosphodiesterase inhibitor endowed with powerful immunomodulatory properties. In this study, we evaluated the effects of this drug on the development of the T-cell-mediated hepatitis inducible in mice by concanavalin A. The results indicated that prophylactic treatment with either 5 or 10 mg/kg rolipram injected intraperitoneally 24 h and 1 h prior to intravenous (i.v.) challenge with 20 mg/kg concanavalin A successfully ameliorated serological and histological signs of liver damage, so that the treated mice showed lower transaminase levels in the plasma and milder mononuclear cell infiltration of the liver as compared to vehicle-treated controls. Moreover, this effect was associated with profound modifications of circulating levels of cytokines released after concanavalin A injection, with the blood levels of interferon-gamma and tumor necrosis factor-alpha being significantly lower and those of interleukin-10 higher than those of the control mice. In particular, the increased blood levels of interleukin-10 might play an important role in the anti-hepatitic effects of rolipram as coadministering this compound with anti-interleukin-10 monoclonal antibody significantly reduced its anti-inflammatory action. These results suggest that rolipram may be useful in the clinical setting for the treatment of cell-mediated immunoinflammatory diseases such as immunoinflammatory hepatitis.
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PMID:Prevention by rolipram of concanavalin A-induced T-cell-dependent hepatitis in mice. 1007 16

A phosphodiesterase inhibitor (PDEI), Ibudilast, which has been in wide use for the management of bronchial asthma and cerebrovascular disease in Japan, was tested for its clinical efficacy on experimental autoimmune encephalomyelitis (EAE) in Dark August rats. The severity of acute EAE was significantly ameliorated by prophylactic oral treatment with Ibudilast (10 mg/kg per day) starting on the day of immunization, although it did not modify the course of the disease when it was given after the onset of the first clinical sign of EAE. Histologically, inflammatory cell infiltration in the lumbar spinal cord was significantly reduced in Ibudilast-treated animals as compared to control animals. Ibudilast mildly suppressed MBP-induced proliferation of T cells in regional lymph nodes, the secretion of interferon-gamma from T cells activated by MBP in CFA, and the secretion of tumor necrosis factor-alpha from macrophages. While the in vitro studies did not suggest difference between Ibudilast and other PDEIs such as rolipram, the clinical dose of Ibudilast is approximately 200-fold higher than that of rolipram and the effective dose of Ibudilast was relatively close to what has been therapeutically used in patients. Thus, Ibudilast may be a candidate for clinical use for patients with multiple sclerosis. 1999 Elsevier Science B.V. All rights reserved.
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PMID:Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. 1022 13

Type IV phosphodiesterase inhibitors are able to suppress EAE. To investigate the effects of this therapy in the central nervous system, we serially analyzed from days 7 to 17 postinoculation the gene expression pattern of tumor necrosis factor (TNF), lymphotoxin, interferon-gamma, interleukin-1beta, the inducible nitric oxide synthase (iNOs), interleukin-10, the vascular cell adhesion molecule-1 (VCAM-1) and the intercellular adhesion molecule-1 (ICAM-1) in the spinal cord of Lewis rats with actively induced EAE, treated with Rolipram. Treated rats had a delayed and milder disease, and reduced numbers of infiltrates in the nervous tissue. The gene expression profile was similar to that of untreated rats, although delayed, with no evidence of IL-10 upregulation during the observation period. The delayed inflammation was not associated with changes in the expression of VCAM-1 and ICAM-1. In peripheral blood mononuclear cells, TNF mRNA levels were decreased and interleukin-10 was unchanged. This therapy did not alter the proliferative ability of T lymphocytes against myelin basic protein. The encephalitogenic potential of splenocytes from treated animals was also unaffected. The high levels of both iNOs mRNA and nitric oxide (NO) found before the appearance of clinical signs, suggests that NO generation might be a contributing factor to the therapeutic benefit achieved by Rolipram in the rat.
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PMID:Type IV phosphodiesterase inhibition in experimental allergic encephalomyelitis of Lewis rats: sequential gene expression analysis of cytokines, adhesion molecules and the inducible nitric oxide synthase. 1038 42

Vesnarinone (OPC-8212) is a synthetic quinolinone derivative with inotropic and immunomodulatory effects. Vesnarinone has been shown to inhibit tumor necrosis factor-alpha (TNF alpha) produced by mitogen stimulated macrophages, and to inhibit phosphodiesterase (PDE) type III in cardiac muscle. TNF alpha and interferon-gamma (IFNgamma) have been implicated in the pathogenesis of autoimmune diseases, and both cytokines are targets for therapeutic intervention. IFNgamma can enhance autoimmune disease through direct effects, and indirectly by priming macrophages to produce TNF alpha. In this study, we demonstrate that while vesnarinone enhances basal TNF alpha levels, it inhibits TNF alpha production in peripheral blood mononuclear cells from multiple sclerosis (MS) patients and healthy donors stimulated with lipopolysaccharide (LPS) or primed with IFNgamma and stimulated with suboptimal doses of LPS. In addition, vesnarinone inhibited TNF alpha production in primary adult human microglial cultures. However, in contrast to rolipram, another TNF alpha inhibiting agent, vesnarinone failed to inhibit TNF alpha production by myelin basic protein specific T-cell lines. As oral TNF inhibitors are currently being considered in the USA for clinical application in MS, the implications of our findings on the development of vesnarinone for treatment of MS are discussed.
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PMID:The effect of vesnarinone on TNF alpha production in human peripheral blood mononuclear cells and microglia: a preclinical study for the treatment of multiple sclerosis. 1040 67

U937 monocytic cells are shown here to express a range of PDE4, cAMP-specific phosphodiesterase (PDE) isoenzymes: the long isoenzymes, PDE4A4, PDE4D5 and PDE4D3, plus the short isoenzyme, PDE4B2. These isoenzymes provide around 76% of the total cAMP PDE activity of U937 cells. The specific activities of the total PDE4A, PDE4B and PDE4D activities were 0.63+/-0.09, 8.8+/-0.2 and 34.4+/-2.9 pmol/min per mg of protein respectively. The PDE4 selective inhibitor, rolipram, inhibited immunopurified PDE4B and PDE4D activities similarly, with IC(50) values of approx. 130 nM and 240 nM respectively. In contrast, rolipram inhibited immunopurified PDE4A activity with a dramatically lower IC(50) value of around 3 nM. Rolipram increased phosphorylation of cAMP-response-element-binding protein (CREB) in U937 cells in a dose-dependent fashion, which implied the presence of both high affinity (IC(50) value approx. 1 nM) and low affinity (IC(50) value approx. 120 nM) components. Rolipram dose-dependently inhibited the interferon-gamma (IFN-gamma)-stimulated phosphorylation of p38 mitogen-activated protein (MAP) kinase in a simple monotonic fashion with an IC(50) value of approx. 290 nM. On this basis, it is suggested that rolipram inhibition of PDE4A4 is involved in regulating CREB phosphorylation but not IFN-gamma-stimulated p38 MAP kinase phosphorylation. PDE4A4 was also selectively activated by challenge of U937 cells with either bacterial lipopolysaccharide (LPS) or IFN-gamma through a process which was attenuated by both wortmannin and rapamycin. It is proposed that the PDE4A4 isoform is involved in compartmentalized cAMP signalling responses in U937 monocytes.
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PMID:Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response-element-binding protein (CREB) and p38 mitogen-activated protein (MAP) kinase in U937 monocytic cells. 1074 88

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological features reminiscent of those seen in multiple sclerosis and thus serves as an animal model for this disease. Inhibition of type IV phosphodiesterase (PDE IV) in animals with this disease has been shown to result in amelioration of disease symptoms. Here we describe the immunomodulatory activity of the novel potent and selective PDE IV inhibitor mesopram. In vitro, mesopram selectively inhibits the activity of type 1 helper T (Th1) cells without affecting cytokine production or proliferation of type 2 helper T (Th2) cells. Administration of mesopram to rodents inhibits EAE in various models. Clinically, EAE is completely suppressed by mesopram in Lewis rats. This is accompanied by a reduction of inflammatory lesions in spinal cord and brain. RT-PCR analysis revealed a marked reduction in the expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the brains of these animals. Furthermore, the ex vivo production of Th1 cytokines by activated spleen cells derived from mesopram-treated animals is significantly reduced compared to vehicle-treated controls. Amelioration of the clinical symptoms is also observed during chronic EAE in mesopram-treated SJL mice as well as in relapsing-remitting EAE in SWXJ mice using a therapeutic treatment regimen. These data demonstrate the anti-inflammatory activity of mesopram and provide a rationale for its clinical development.
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PMID:The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents. 1090 Mar 47


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