Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycerylphosphorylcholine (GPC) phosphocholine phosphodiesterase activity (EC 3.1.4.38) is significantly reduced in multiple sclerosis plaques compared to adjacent tissue with a P less than 0.01 based upon the Student-Newman-Keuls or Tukey test. This finding is in accord with the proposal that this particular form of the enzyme is myelin-specific. Similar activities for GPC phosphocholine phosphodiesterase were obtained with samples from various regions of the same individual brain.
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PMID:Glycerylphosphocholine phosphocholine phosphodiesterase activity is reduced in multiple sclerosis plaques. 216 15

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that serves as a model for the human disease multiple sclerosis. We evaluated rolipram, a type IV phosphodiesterase inhibitor, for its efficacy in preventing EAE in the common marmoset Callithrix jacchus. In a blinded experimental design, clinical signs of EAE developed within 17 days of immunization with human white matter in two placebo-treated animals but in none of three monkeys that received rolipram (10 mg/kg s.c. every other day) beginning 1 week after immunization. In controls, signs of EAE were associated with development of cerebrospinal fluid pleocytosis and cerebral MRI abnormalities. In the treatment group, there was sustained protection from clinical EAE, transient cerebrospinal fluid pleocytosis in only one of three animals, no MRI abnormality, and marked reduction in histopathologic findings. Rolipram-treated and control animals equally developed circulating antibodies to myelin basic protein. Thus, inhibition of type IV phosphodiesterase, initiated after sensitization to central nervous system antigens, protected against autoimmune demyelinating disease.
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PMID:Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor. 753 38

In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) the cytokines tumour necrosis factor-alpha (TNF), lymphotoxin-alpha (LT), and interferon-gamma (IFN-gamma) 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-gamma 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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PMID:The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. 758 35

To extend our evaluation of insulin-like growth factor-1 (IGF-1) treatment for human demyelinating diseases, we compared effects of s.c. and i.v. IGF-1 in an in vivo model with lesions resembling those seen in multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats with an emulsion containing guinea pig spinal cord and treatment with placebo or with s.c. or i.v. IGF-1 was started when definite clinical weakness was present. IGF-I given subcutaneously significantly reduced clinical deficits and lesion severity. The clinical improvement, as measured by clinical deficit scores, stride lengths and exercise wheel rotations, was evident in 48 hrs and was comparable to that produced by the same IGF-I dose administered intravenously. Subcutaneously administered IGF-I also increased relative mRNA levels of myelin basic protein (MBP), proteolipid (PLP) and 2',3' cyclic nucleotide 3'-phosphodiesterase (CNP), thereby promoting myelin regeneration. We conclude that s.c. IGF-I produces dramatic improvement in acute, demyelinating EAE. Our results also suggest that this growth factor may be useful in treating multiple sclerosis patients with active demyelination.
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PMID:Insulin-like growth factor-I given subcutaneously reduces clinical deficits, decreases lesion severity and upregulates synthesis of myelin proteins in experimental autoimmune encephalomyelitis. 861 86

The outcome of immune responses can be predicted by the lymphokine production pattern of the participating cells. Cytokines of the T helper type 1 (Th1) cells mediate inflammatory responses and delayed-type hypersensitivity (DTH), whereas Th2-like T cells predominantly produce cytokines, which stimulate antibody production by B cells. Immunoregulatory therapy of autoimmune diseases with unknown antigens may be achieved by inhibiting the production of inflammatory cytokines and induction of protective cytokines of Th2-like T cells. To determine the immunoregulatory capacity of the phosphodiesterase inhibitor pentoxifylline (PTX), which is known to suppress the production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), this drug was used in mitogen and antigen-stimulated lymphocyte cultures as well as in patients with multiple sclerosis. PTX significantly decreased TNF-alpha and interleukin-12 (IL-12), whereas it increased IL-4 and IL-10 production. In addition, PTX inhibited cell proliferation, which was associated with a marked reduction in CD25 (IL-2 receptor alpha-chain) and CD54 (intercellular adhesion molecule-1; ICAM-1) expression. Increasing doses of PTX significantly reduced TNF-alpha and IL-12 mRNA expression of blood mononuclear cells, but increased IL-4 and IL-10 expression in eight patients with relapsing-remitting multiple sclerosis. These results indicate that PTX modulates immune reactions favouring a Th2-like response and may therefore be useful for the treatment of autoimmune diseases with a dominant Th1-like T cell response.
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PMID:Pentoxifylline, a phosphodiesterase inhibitor, induces immune deviation in patients with multiple sclerosis. 863 62

Experimental autoimmune encephalomyelitis (EAE) in Lewis rats, an animal model mimicking some aspects of multiple sclerosis, was treated with the type IV-specific phosphodiesterase inhibitor Rolipram. Actively induced EAE evoked by immunization with myelin basic protein (MBP) in complete Freund's adjuvant was delayed but only slightly ameliorated in its maximal severity by preventive treatment with Rolipram (2 x 3 mg/kg per day) starting on the day of immunization. Therapeutic administration of Rolipram (2 x 5 mg/kg per day) was begun within hours after onset of first clinical signs of EAE but could not modify the further course of the disease. Both doses had significant side effects. Injection of 5 mg Rolipram/kg provoked transient slackening and unsteady gait while chronic application of 6 mg/kg/day strongly accelerated the weight gain in adolescent rats. EAE adoptively transferred by injection of encephalitogenic T line blasts was shortened and significantly suppressed in its severity by application of Rolipram (2 x 5 mg/kg per day) starting on the day of cell transfer. In corresponding lumbar spinal cord sections density of inflammatory infiltration by T cells and macrophages was reduced. Rolipram did not prevent generation of an antigen-specific immune response in vivo. In vitro the drug inconsistently inhibited MBP-induced activation of encephalitogenic T cells. TNF-alpha secretion by encephalitogenic T cells was limited only when T cell proliferation was also affected. In contrast, TNF-alpha production by LPS-activated macrophages was consistently and markedly suppressed by Rolipram. However, since the encephalitogenic T line cells produced at least 100 times more TNF-alpha than the same number of Rolipram-sensitive macrophages, the impact of Rolipram on the total amount of TNF-alpha synthesized in EAE may be limited. Together with our histological findings, the data suggest that relevant immunosuppressive mechanisms of Rolipram may be the inhibition of migration of leukocytes into the central nervous system and to some extent its inhibitory effect on T cell proliferation and macrophage activity. The downregulatory effects of Rolipram may be partially counteracted by its augmenting impact on the production of nitric oxide by macrophages.
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PMID:Preventive but not therapeutic application of Rolipram ameliorates experimental autoimmune encephalomyelitis in Lewis rats. 878 54

Susceptibility to multiple sclerosis (MS) is widely held to have a genetic component. Possible candidate genes conferring this susceptibility include those coding for proteins specific to central nervous system (CNS) myelin. 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNPase) is an enzyme found at high concentrations in CNS myelin, however its function is unknown. The amino acid sequence of CNPase shows a C-terminal motif characteristic of proteins involved in signal transduction pathways, suggesting a key role in myelin function. We have analysed the entire expressed sequence of the human CNPase gene in patients with multiple sclerosis and in healthy controls using single strand conformation polymorphism (SSCP) analysis. Nine previously undescribed mutations were detected, most of these occurred with equal frequency in both groups. However, a T-->C transition at nucleotide position 4306 in the region of the gene coding for the 3' untranslated region of the mature mRNA was found in a homozygous form in two out of 54 patients but in none of 100 controls. While the significance of this is unclear, it would appear unlikely that mutations in the expressed regions of the human CPNase gene contribute to genetic susceptibility to MS in the majority of sufferers.
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PMID:Analysis of polymorphisms of the 2',3'-cyclic nucleotide-3'-phosphodiesterase gene in patients with multiple sclerosis. 905 Mar 59

Multiple sclerosis is an autoimmune disease with inflammatory lesions localized to the white matter of the central nervous system. Early on, the disease is characterized by episodes of exacerbations and remissions. During exacerbations there is an acute inflammatory infiltrate characterized by the presence of mononuclear cells, monocytes, and T lymphocytes. These cells produce proinflammatory cytokines that have been implicated in the amplification of the inflammatory response as well as in the damage of oligodendrocytes. The inflammation ultimately results in loss of myelin and oligodendrocyte cell death (demyelination). Thus therapies aimed at preventing the inflammatory response may have a beneficial effect on the course of the disease. One such therapy is treatment with inhibitors of phosphodiesterase type IV. These drugs have proven to be extremely effective in the prevention and treatment of experimental allergic encephalomyelitis, the animal model for multiple sclerosis. These experiments, as well as other data discussed here, provide a rationale for the treatment of multiple sclerosis with inhibitors of phosphodiesterase type IV.
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PMID:Phosphodiesterase type IV inhibitors in the treatment of multiple sclerosis. 908 27

It was recently demonstrated that selective phosphodiesterase type 4 (PDE4) inhibition suppresses the clinical manifestations of acute experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), and inhibits the production of tumor necrosis factor-alpha (TNF-alpha), a pathogenetically central cytokine. Since the most common presentation of MS in humans is a relapsing-remitting course, we investigated the therapeutic potential of PDE4 inhibition in the relapsing-remitting EAE model of the SJL mouse. Administration of rolipram, the prototypic PDE4 inhibitor, reduced the clinical signs of EAE during both the initial episode of disease and subsequent relapses. In parallel, there was marked reduction of demyelination and also less inflammation throughout the central nervous system (CNS) of rolipram-treated animals. Gene expression of proinflammatory cytokines in the CNS was reduced in most of the rolipram-treated animals. Additional experiments demonstrated that PDE4 inhibition acted principally by inhibiting the secretion of Th1 cytokines, however, the encephalitogenic potential of myelin basic protein-specific T cells was not impaired. Our findings suggest that PDE4 inhibitors are a promising cytokine-directed therapy in chronic demyelinating disease.
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PMID:Therapeutic potential of phosphodiesterase type 4 inhibition in chronic autoimmune demyelinating disease. 935 47

Multiple sclerosis (MS) is characterized by intra-blood-brain barrier immunoglobulin synthesis that persists lifelong. Subcellular fractionation and two-dimensional electrophoresis were used in conjunction with immune precipitation and immunoblotting to identify antigenic determinants for this immunoglobulin. We report that 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a protein associated with oligodendrocyte/myelin membranes, also present in lymphocytes and retina, is one major target for the humoral response. Antibodies to CNP are detected in sera of 74% of MS patients. The antibodies are IgM and are present in serum in high titer as well as in cerebrospinal fluid. The antibody response is temporally persistent, consistent with systemic immune activation and persistent antigenic stimulation. Moreover, CNP is isolated as an immune complex from MS brain. CNP is expressed as two isoforms, with CNPII identical to CNPI but with a 20-amino acid extension at the amino terminus of CNPII; however, the antibody response is exclusively restricted to CNPI. In contrast, both isoforms bind the C3 complement, providing a plausible mechanism in MS central nervous system (CNS) for opsonization of myelin membrane CNP, mediated via the C3 receptor, and phagocytosis of CNP-Ig immune complexes, mediated by membrane Ig Fc receptors of macrophages and CNS microglia.
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PMID:Dual implication of 2',3'-cyclic nucleotide 3' phosphodiesterase as major autoantigen and C3 complement-binding protein in the pathogenesis of multiple sclerosis. 957 57


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