The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents

Dinter, Harald; Tse, Jenny; Halks-Miller, Meredith; Asarnow, David M.; Onuffer, James; Faulds, Daryl; Mitrovic, Branislava; Kirsch, G.; Laurent, Henry; Esperling, Peter; Seidelmann, Dieter; Ottow, Eckhard; Schneider, Havah; Tuohy, Vincent K.; Wachtel, H.; Perez, Hector D.

doi:10.1016/s0165-5728(00)00265-4

Cited by 49 publications

(38 citation statements)

References 44 publications

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“…Results from clinical trials with the specific type-4 phosphodiesterase inhibitor airflow in patients with chronic obstructive pulmonary disease are positive (Hay, 2000;Compton et al, 2001). A recent study reports on the successful inhibition of experimental autoimmune encephalitis in rodents by mesopram (Dinter et al, 2000). Future indications for these agents as anti-inflammatory drugs could comprise rheumatoid arthritis (Nyman et al, 1997;Francischi et al, 2000;Hogan et al, 2001) and, as demonstrated here, chronic inflammatory bowel diseases.…”

Section: Discussionmentioning

confidence: 67%

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The Specific Type-4 Phosphodiesterase Inhibitor Mesopram Alleviates Experimental Colitis in Mice

Loher¹,

Schmall²,

Freytag³

et al. 2003

J Pharmacol Exp Ther

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Mesopram, a specific inhibitor of type-4 phosphodiesterase, decreases the synthesis of tumor necrosis factor-␣ (TNF-␣) and interferon-␥ (IFN-␥). In the present study, we investigated the effect of mesopram in dextran sulfate sodium (DSS)-induced murine colitis. In the preventive model, colitis was induced by DSS simultaneously with the application of mesopram in BALB/c mice. In the therapeutic model, colitis was induced in BALB/c mice by DSS over 7 days. At day 8, DSS was discontinued, and treatment was started. Mesopram was applied intraperitoneally or orally. The clinical score was calculated daily during the course of each study. Post mortem, colon length, histologic score, and expression of TNF-␣ and IFN-␥ in colons were determined. In the preventive model, mesopram significantly reduced the maximal clinical score, decreased colon shortening, and the histologic score. A dose finding study, using the preventive model, showed that most clinical and post mortem benefit was achieved with 50 mg/kg mesopram compared with 2 and 10 mg/kg. In the therapeutic model, i.p. mesopram treatment led to a significant reduction of clinical score. Both, i.p. and p.o. mesopram significantly reversed DSSinduced colon shortening and reduced the ex vivo colonic production of IFN-␥. We conclude that the specific type-4 phosphodiesterase inhibitor mesopram ameliorates murine colitis both in a preventive and a therapeutic setting.

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Section: Discussionmentioning

confidence: 67%

“…Mesopram is a novel potent and selective enantiomeric PDE4 inhibitor. It has been shown to be effective in the treatment of experimental autoimmune encephalitis in rodents (Dinter et al, 2000).…”

mentioning

confidence: 99%

The Specific Type-4 Phosphodiesterase Inhibitor Mesopram Alleviates Experimental Colitis in Mice

Loher¹,

Schmall²,

Freytag³

et al. 2003

J Pharmacol Exp Ther

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“…Since the cytokine milieu at the time of initial allergen sensitization can determine the phenotype of the immune response to an allergen, alterations in this milieu by PTX could account for its effect on AHR. Although PDE 4-specific inhibitors have been shown to inhibit Th2 cytokine expression by Th2 cells and by PBMCs from atopic individuals, they have also been shown to inhibit Th1 cytokine production by Th1 cells in vitro and in animal models of Th1-mediated disease in vivo (63)(64)(65)(66)(67)(68)(69)(70)(71)(72). For the nonspecific PDE inhibitor PTX, data indicate that both in vitro and in vivo, in naive and differentiated cells, PTX inhibits Th1 cytokine production and has either no effect or an enhancing effect on Th2 cytokine production (18 -22, 24 -30).…”

Section: Discussionmentioning

confidence: 99%

Administration of Pentoxifylline During Allergen Sensitization Dissociates Pulmonary Allergic Inflammation from Airway Hyperresponsiveness

Fleming

Ciota

et al. 2001

The Journal of Immunology

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Asthma, a chronic inflammatory disease characterized by intermittent, reversible airflow obstruction and airway hyperresponsiveness (AHR), is classically characterized by an excess of Th2 cytokines (IL-13, IL-4) and depletion of Th1 cytokines (IFN-γ, IL-12). Recent studies indicating an important role for Th1 immunity in the development of AHR with allergic inflammation suggest that Th1/Th2 balance may be important in determining the association of AHR with allergic inflammation. We hypothesized that administration of pentoxifylline (PTX), a phosphodiesterase inhibitor known to inhibit Th1 cytokine production, during allergen (OVA) sensitization and challenge would lead to attenuation of AHR in a murine model of allergic pulmonary inflammation. We found that PTX treatment led to attenuation of AHR when administered at the time of allergen sensitization without affecting other hallmarks of pulmonary allergic inflammation. Attenuation of AHR with PTX treatment was found in the presence of elevated bronchoalveolar lavage fluid levels of the Th2 cytokine IL-13 and decreased levels of the Th1 cytokine IFN-γ. PTX treatment during allergen sensitization leads to a divergence of AHR and pulmonary inflammation following allergen challenge.

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“…Although these compounds were originally developed for reactive airway diseases, 14,15 PDE4 inhibitors are also being evaluated in autoimmune diseases 16 and 2 additional B-cell malignancies, chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia (ALL). 17,18 In vitro analyses of primary CLL samples and ALL cell lines suggest that inhibition of PDE4 increases tumor cell apoptosis, underscoring the potential of this possible therapeutic target in DLBCL.…”

Section: Introductionmentioning

confidence: 99%

The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT–dependent apoptosis in diffuse large B-cell lymphoma

Smith

Wang

Wilkinson

et al. 2005

Blood

130

149

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Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. Advances in the treatment of this disease will require the identification of novel therapeutic targets. We previously defined an expression signature of outcome in DLBCL and found that the phosphodiesterase PDE4B was overexpressed in fatal/refractory tumors. Phosphodiesterase 4B (PDE4B) inactivates the second messenger cyclic adenosine 3,5 monophosphate (cAMP) and abrogates its inhibitory effects in B lymphocytes. Hence, DLBCLs that express high PDE4B levels may be resistant to cAMP-induced apoptosis, contributing to their less favorable outcome. Herein, we confirmed the riskrelated expression of PDE4B in an independent series of primary DLBCLs and defined the enzyme's role in modulating cAMP-induced apoptosis in parental DLBCL cell lines or those reconstituted with wild-type or mutant PDE4B. The cAMP-mediated apoptosis of DLBCLs was largely independent of the previously described cAMP effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), but associated with inhibition of the phosphatidylinosi- IntroductionDiffuse large B-cell lymphoma (DLBCL) is a common and heterogeneous B-lymphoid malignancy. 1 Although a subset of patients with DLBCL are cured with combination chemotherapy, the remainder die of their disease. Therefore, additional understanding of the molecular and cellular heterogeneity of DLBCL and identification of potential rational therapeutic targets are needed. Recently, transcriptional profiling of DLBCL has been used to highlight similarities between subsets of tumors and normal B cells 2 and to identify features associated with unfavorable responses to empiric combination chemotherapy. 2,3 In a pilot study of DLBCL outcome signatures, 3 one of the most prominently overexpressed genes in fatal/refractory DLBCL was the phosphodiesterase, PDE4B.Phosphodiesterases (PDEs) catalyze the hydrolysis of cyclic adenosine 3Ј,5Ј monophosphate (cAMP) and cyclic guanosine 3Ј,5Ј monophosphate (cGMP), inactivating these second messengers. 4 The PDE superfamily is subgrouped into 11 families that include at least 20 different genes and 50 unique isoforms. Of these PDE gene families, 3 are cAMP specific: PDE4, PDE7, and PDE8. 5 Isoforms of the PDE4 family are the major inactivators of cellular cAMP and the predominant phosphodiesterases in lymphocytes. 5,6 There are 4 PDE4 proteins, A to D, encoded by different genes and at least 3 different isoforms of PDE4B, PDE4B1, B2, and B3. These isoforms contain variable numbers of highly conserved amino terminal regions, PDE4B1 and B3 (long forms) including upstream conserved regions 1 and 2 (UCR1 and 2), and PDE4B2 (short form) containing only UCR2. The UCR1/UCR2 regions function as regulatory domains that control the conformation and activity of the catalytic domain, at least in part via the phosphorylation of a single serine residue at the amino terminus of UCR1 by protein kinase A (PKA). 5,6 Further details on the structure and regulation of the PDE4 family c...

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The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents

Cited by 49 publications

References 44 publications

The Specific Type-4 Phosphodiesterase Inhibitor Mesopram Alleviates Experimental Colitis in Mice

The Specific Type-4 Phosphodiesterase Inhibitor Mesopram Alleviates Experimental Colitis in Mice

Administration of Pentoxifylline During Allergen Sensitization Dissociates Pulmonary Allergic Inflammation from Airway Hyperresponsiveness

The phosphodiesterase PDE4B limits cAMP-associated PI3K/AKT–dependent apoptosis in diffuse large B-cell lymphoma

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