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)

Nitric oxide (NO) has been implicated in the etiopathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), and inhibition of NO synthesis has been proposed to be a possible mechanism of action of drugs to treat MS. In the present study, we investigated the inhibitory effect on NO synthesis of various steroids, cytokines and drugs used or proposed for the treatment of MS. As a model system, we used primary rat microglial cells which produce NO synthase and subsequently release NO upon stimulation with lipopolysaccharide (LPS). Among the substances tested, the glucocorticoids prednisone, hydrocortisone, dexamethasone and progesterone as well as transforming growth factor-beta (TGF-beta) dose-dependently inhibited LPS-induced nitric oxide synthase (iNOS) and NO synthesis. In contrast, COP-1, the phosphodiesterase inhibitors rolipram and pentoxifylline, the cytokines interleukin-10 (IL-10) and interferon-beta (IFN-beta) as well as the steroids beta-estradiol, testosterone, and dehydroepiandrosterone (DHEA) showed no inhibitory effect. Cholesterol slightly, but not significantly, increased LPS-induced nitric oxide synthesis. We conclude from the present study that with respect to treatment of MS, inhibition of NO synthesis may be an important mechanism of action of glucocorticoids and transforming growth factor-beta, but not of other drugs used or proposed to treat MS.
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PMID:Inhibition of LPS-induced iNOS and NO synthesis in primary rat microglial cells. 1242 93

Upregulation of the cAMP/protein kinase A (PKA) pathway has been shown to result in decreased proliferation, increased differentiation, and subsequent apoptosis of malignant glioma cells. Conventional cAMP analogs, however, are difficult to use in a clinical setting. Therefore, we investigated the effects of rolipram, a drug that has undergone clinical trials as an antidepressant and has also been proposed as a treatment for multiple sclerosis. Rolipram acts as a specific inhibitor of type IV phosphodiesterase (PDE4), leading to increased intracellular levels of cAMP. We report that the inhibition of PDE4 by rolipram results in the activation of the cAMP/PKA pathway, with potent stimulation of a reporter gene containing a cAMP-responsive element in its promoter region. Further, treatment of the human glioma cell line A-172 with rolipram results in increased expression of the cell cycle inhibitors p21(Cip1) and p27(KiP1), and decreased activity of cdk2, a cyclin-dependent kinase essential for cell cycle progression. As a result, the proliferation of A-172 cells is inhibited, with induction of a Gl block. Eventually, rolipram-treated A-172 cells undergo differentiation, which is followed by apoptotic cell death. As we observe this effect with other glioma cell cultures as well, our results suggest that rolipram could prove useful as a novel differentiating agent with both cytostatic and cytotoxic potential in the treatment of malignant gliomas.
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PMID:The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells. 1243 76

Although patients with multiple sclerosis (MS) are likely to have problems with bladder, bowel and sexual function, these problems have often been neglected in the past. Bladder dysfunction produces symptoms of urgency, frequency and urge incontinence (due to bladder overactivity and incomplete emptying), and is found in up to 75% of patients with MS. The mainstay of drug treatment for neurogenic bladder overactivity is anticholinergic medication, although intravesical treatments have also been proposed, such as the vanilloids and botulinum toxin, as well as sublingual cannibanoids. There has been much progress with pro-erectile agents in recent years, notably the use of sildenafil citrate, which has been shown to be particularly efficacious in these patients. Other agents include apomorphine hydrochloride and newer phosphodiesterase 5 inhibitors; however, the efficacy of these drugs in patients with MS remains to be proven. Research in female sexual dysfunction is also progressing, although this aspect of patient well being has only recently been addressed; the reported development of a classification system for the condition is likely to help categorise future treatments. Unlike bladder and sexual dysfunction, there have been rather limited advances in the treatment of faecal incontinence and constipation specifically for patients with MS, despite a prevalence of up to 50%. This review highlights the strategies for these types dysfunction commonly seen in patients with MS, with report of recent pharmacological developments.
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PMID:Bladder, bowel and sexual dysfunction in multiple sclerosis: management strategies. 1251 63

The effects of phosphodiesterase inhibitors (PDEIs) on interleukin (IL)-12 production by microglia, antigen-presenting cells in the central nervous system (CNS), were examined to learn how they affect T cell differentiation in the CNS. PDEIs significantly suppressed the microglial IL-12 production, as determined by reverse transcriptase-polymerase chain reaction for IL-12 p35 and p40 mRNA expression and by an ELISA specific for IL-12 functional heterodimer, p70. In addition, the PDEI ibudilast also suppressed interferon-gamma, but not IL-4 or IL-10, production by myelin oligodendrocyte glycoprotein (MOG)-specific T cells reactivated with MOG in the presence of microglia. Thus, PDEIs may also suppress differentiation of T helper 1 (Th1) in the CNS. PDEIs can be of use for future therapeutic strategy to treat Th1-mediated diseases, such as multiple sclerosis.
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PMID:Phosphodiesterase inhibitors suppress IL-12 production with microglia and T helper 1 development. 1466 69

Interferon-beta (IFNbeta) reduces exacerbations of the relapsing-remitting form of multiple sclerosis (MS), but the exact mechanisms by which it exerts its beneficial effects are unknown. In this study, we examined the effects of IFNbeta on microglial functions, as either antigen presenting cells or effector cells for inflammatory demyelination. IFNbeta significantly suppressed the expression of class II MHC antigen and the co-stimulatory molecule B7-1 in microglia. It also suppressed microglial IL-12 production and differentiation of myelin oligodendrocyte glycoprotein (MOG)-sensitized T cells into the T helper 1 phenotype, which use microglia as antigen presenting cells. However, IFNbeta significantly and dose-dependently enhanced the production of inflammatory mediators for demyelination, such as TNFalpha, IL-1beta, IL-6, and nitric oxide (NO). The upregulation of inflammatory mediators was effectively suppressed with a phosphodiesterase inhibitor. Thus, IFNbeta may exert its suppressive effects in the induction phase, but not in the effector phase of MS. Side effects of IFNbeta treatment may be due to elevation of pro-inflammatory cytokines, and may be reduced by co-treatment with phosphodiesterase inhibitors.
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PMID:Effects of interferon-beta on microglial functions as inflammatory and antigen presenting cells in the central nervous system. 1499 51

Two-dimensional gel electrophoresis and peptide mass fingerprinting were used to identify proteins in cerebrospinal fluid (CSF) pooled from three patients with multiple sclerosis (MS) and in CSF pooled from three patients with non-MS inflammatory central nervous system (CNS) disorders. Resolution of CSF proteins on three pH gradients (3-10, 4-7 and 6-11) enabled identification of a total of 430 spots in the MS CSF proteome that represented 61 distinct proteins. The gels containing MS CSF revealed 103 protein spots that were not seen on control gels. All but four of these 103 spots were proteins known to be present in normal human CSF. The four exceptions were: CRTAC-IB (cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a calcium binding cell signalling glycoprotein), and autotaxin t (a phosphodiesterase). It remains unknown whether these four proteins are related to the cause and pathogenesis of MS.
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PMID:Proteomic analysis of multiple sclerosis cerebrospinal fluid. 1522 87

Demyelination is a hallmark of several human diseases, including multiple sclerosis. To understand better the process of demyelination and remyelination, we explored the use of an in vitro organotypic cerebellar slice culture system. Parasagittal slices of postnatal Day 10 (P10) rat cerebella cultured in vitro demonstrated significant myelination after 1 week in culture. Treatment of the cultures at 7 days in vitro (DIV) with the bioactive lipid lysolecithin (lysophosphatidylcholine) for 15-17 hr in vitro produced marked demyelination. This demyelination was observed by immunostaining for the myelin components myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase). After a transient demyelinating insult with lysolecithin in vitro, the cultures recovered with oligodendrocyte differentiation recapitulating a normal time course; there was initially re-expression of CNPase and MBP during this recovery, and this was followed by MOG. In addition, there seemed to be some limited remyelination during the recovery phase. Lysolecithin thus induces demyelination in an in vitro organotypic cerebellar slice culture system, providing a model system for studying myelination, demyelination, and remyelination in vitro.
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PMID:Lysolecithin induces demyelination in vitro in a cerebellar slice culture system. 1537 14

We investigated the immunoregulatory effects of ibudilast, a nonselective phosphodiesterase inhibitor, at a clinically applicable dose (60 mg/day p.o. for four weeks) in multiple sclerosis (MS) patients. Sensitive real-time PCR for quantifying cytokine mRNA in the blood CD4+ cells revealed that the ibudilast monotherapy significantly reduced tumour necrosis factor-alpha and interferon (IFN)-gamma mRNA and the IFN-gamma/interleukin-4 mRNA ratio, suggesting a shift in the cytokine profile from Th1 toward Th2 dominancy. In a flow cytometric analysis, natural killer T cells, which have been reported to relate to Th2 responses in MS and its animal model (experimental autoimmune encephalomyelitis), increased significantly after the therapy. None of the significant immunological changes were seen in healthy subjects or untreated MS patients. Ibudilast may be a promising therapy for MS and its clinical effects warrant further study.
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PMID:Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. 1547 63

Several neurodegenerative disorders, such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease, are associated with inflammatory damage. The complex process of neuroinflammation involves various components of the immune system and the central nervous system. Particularly, brain astrocytes and microglial cells generate several inflammatory mediators like cytokines, leukotrienes, superoxide radicals, eicasonoids, and the components of the complement cascade. Complement plays an important role in the etiology of most of the neuroinflammatory disorders. To prevent long-term dysfunction inflammation in the central nervous system must be modulated with neuroprotective agents such as nonsteroidal anti-inflammatory drugs, steroids, phenolic thiazoles, nitrones, catechins, nitric oxide synthetase inhibitors, flavonoids, and phosphodiesterase inhibitors. Few drugs are found to be effective and their therapeutic benefit is hampered by side effects. Most of the neuroprotective agents are free radical scavengers and many inhibit only one or two aspects of inflammation. The complement inhibitory activity of most of these agents is either unknown or not established. Thus, there is doubt regarding their therapeutic value in most of the inflammatory disorders in which complement plays a major role. In this context the role of a multifunctional protein, vaccinia virus complement control protein (VCP), is quite significant as it may play a pivotal role in the treatment of several neuroinflammatory disorders. VCP is known to inhibit both complement pathways involved in inflammation. It is also known to inhibit cytokines and chemokines in inflammation. Our recent studies on rats demonstrate that VCP administration inhibits macrophage infiltration, reduces spinal cord destruction, and improves motor skills associated with spinal cord injury, establishing VCP as a strong candidate for neuroprotection. Thus, complement inhibitors such as VCP can serve as neuroprotective agents in inflammation associated with several neurodegenerative disorders.
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PMID:Neuroprotection from complement-mediated inflammatory damage. 1568 6

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is thought that autoimmunity plays a major role in the development of the disease. Despite understanding MS as the cell-mediated autoimmune disease, recent studies suggest a role of humoral response in MS pathogenesis. The contribution of antibodies with anti-MOG specificity in the pathology of EAE (experimental allergic encephalomyelitis), an animal model of MS, in rodents and recently in primates has been demonstrated. B lymphocytes, plasma cells, and autoantibodies reacting with myelin proteins are present in the chronic and active plaques of MS patients. These antibodies, which recognize myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), myelin-oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP), 2',3' cyclic nucleotide 3'-phosphodiesterase (CNP), and transaldolase (TAL), have been identified mostly in cerebrospinal fluid and in serum. So far, the antibodies directed against MBP, MOG, and OSP have been characterized in detail. However, the role of autoantibodies in MS pathogenesis is still controversial. A direct role in the demyelination process, by the activation of complement and cytotoxic cells, has been shown only for the anti-MOG antibodies. Identification of the antigens and epitopes targeting the autoimmune response in MS is of great importance, not only for understanding of MS pathology, but also for potential therapeutic use. Recently, antigen therapy trials have been conducted in MS patients. It seems, however, that only the recognition of the individual immunological response in each MS patient, including autoantigens and the subspecificity of autoreactive T and B lymphocytes, can allow for an effective fight against this destructive disease.
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PMID:[Epitopes on myelin proteins recognized by autoantibodies present in multiple sclerosis patients]. 1576 8


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