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)

The neurotransmitter, pituitary adenylate cyclase-activating polypeptide (PACAP), is present in the rat adrenal medulla and is a potent stimulus for catecholamine secretion. Previous studies have suggested that neurally derived signals stimulate proliferation of chromaffin cells in adult rats. To determine whether PACAP might be involved in mitogenic signalling, its effects on bromodeoxyuridine incorporation were studied in adrenal medullary cell cultures from adult female rats. Both PACAP 27 and PACAP 38 are able to stimulate proliferation of adult rat chromaffin cells in vitro, either alone or in conjunction with PMA, an activator of protein kinase C. BrdU-labelled nuclei are observed in both epinephrine and norepinephrine cells, and proliferation of both cell types is stimulated by the same concentrations of PACAP that elicit secretion of catecholamines. The mitogenic effects of PACAP are potentiated by indolidan, a phosphodiesterase inhibitor known to cause pheochromocytomas in rats, and are inhibited by H-89, an inhibitor of protein kinase A. Mitogenic concentrations of PACAP inhibit mitogenic effects of nerve growth factor. These findings support the hypothesis that neurally derived signals regulate chromaffin cell proliferation in adult rats. Indolidan and a variety of nongenotoxic agents that cause pheochromocytomas in rats may do so indirectly by increasing neurally mediated chromaffin cell turnover. The antagonism between PACAP and NGF suggests that neurotransmitters may supersede growth factors in regulating chromaffin cell proliferation during development by suppressing or co-opting portions of growth factor signaling pathways.
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PMID:Mitogenic and antimitogenic effects of pituitary adenylate cyclase-activating polypeptide (PACAP) in adult rat chromaffin cell cultures. 762 29

1. Adenosine is an endogenous neuroprotective agent; stimulation of A1 receptors decreases excitatory amino acid neurotransmission and stimulation of A2 receptors inhibits platelet and neutrophil activation and promotes vasodilation. 2. Post-ischemic administration of propentofylline (HWA 285) reduces neuronal damage in gerbils and improves glucose metabolism in all regions of brain in acute stroke patients. 3. Propentofylline inhibits the transport of adenosine into cultured cells and increases extracellular adenosine concentrations in ischemic brain. Thus, enhanced stimulation of adenosine receptors may account for some of the neuroprotective effects of this compound. 4. Propentofylline inhibits free radical production by cultivated microglia cells, stimulates nerve growth factor production and inhibits cAMP-phosphodiesterase activity. These effects may also be important for neuroprotection.
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PMID:Propentofylline: a nucleoside transport inhibitor with neuroprotective effects in cerebral ischemia. 787 26

The effects of chronic treatment (6-8 days) with a phosphodiesterase inhibitor, rolipram, on the expression of voltage-dependent Ca2+ channels, nicotinic acetylcholine (ACh) receptors and 5-hydroxytryptamine (5-HT) receptors were investigated in PC12 cells. The results were compared with the effects of nerve growth factor (NGF), 8-bromo-cyclic AMP (8-Br-cAMP) and phorbol 12-myristate 13-acetate (PMA). In the morphological study rolipram, at a high concentration (100 microM) induced the extension of neurites. A similar result was obtained in 8-Br-cAMP (1 mM)-treated cells. Rolipram, at a low concentration (10 microM) or PMA (10(-7) M) did not induce obvious morphological change. NGF (100 ng/ml) induced the extension of long neurites and the formation of neural networks. Rolipram (100 microM) increased the current density (pA/pF) of voltage dependent Ca2+ current (ICa). Both NGF and 8-Br-cAMP also increased the current density of ICa, whereas PMA did not. NGF increased the current density of the nicotinic ACh response whereas rolipram, 8-Br-cAMP and PMA decreased. Rolipram (100 microM), NGF (100 ng/ml), and 8-Br-cAMP (1 mM) increased the current density of the 5-HT response whereas the effect of PMA (100 nM) was slight. The results suggest that rolipram is able to contribute to the neuronal development by increasing intracellular cAMP as well as 8-Br-cAMP. Consequently, rolipram behaves like a neurotrophic factor in cultured PC12 cells.
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PMID:Rolipram enhances the development of voltage-dependent Ca2+ current and serotonin-induced current in rat pheochromocytoma cells. 840 99

Neuropeptide Y and nitric oxide (NO) synthase are colocalized in nervous tissues. We tested the hypothesis whether or not NO might be involved in the release of neuropeptide Y. Neuropeptide Y concentration in the supernatant of PC12 rat pheochromocytoma cells, shown to express NO synthase I by immunohistochemistry, rose threefold in a time- and dose-dependent manner following sodiumnitroprusside and 3-morpholinosydnonimine (SIN-1) incubation. Neuropeptide Y mRNA expression was induced by NO-donors as a function of incubation-time. Neuropeptide Y production rose fivefold with zaprinast, an inhibitor of the phosphodiesterase V and threefold with nerve growth factor (NGF). Combined application of zaprinast and NGF did not further increase neuropeptide Y production while combination of zaprinast and sodiumnitroprusside potentiated the NO effect on neuropeptide Y release. The data suggest that NO regulates neuropeptide Y secretion of PC12 pheochromocytoma cells on the mRNA level.
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PMID:Stimulation of neuropeptide Y release in rat pheochromocytoma cells by nitric oxide. 927 94

Injury of peripheral nerves induces expression of several pro-protein convertases (PCs) involved in processing of precursor proteins into their diverse active end-products. In this study, the focus was on convertase PC1 which, although undetectable in control nerves, is strongly induced in injured nerves. High concentrations of PC1 mRNA of 9.0, 5.5, 3.0, 2.5 and 1.6 kb were observed on day 4 post-lesion in proximal and distal segments. By in situ hybridization PC1 mRNA was detected in most of endoneurial cells, which were further identified by immunocytochemistry as myelin 2', 3'-cyclic nucleotide 3'-phosphodiesterase containing Schwann cells. PC1 mRNA and protein were also present in cultured Schwann cells also containing convertases PC5, furin and PC7 as well as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). Mostly unprocessed pro-NGF of 35 kDa and pro-BDNF of 35 kDa were found on Western blotting of Schwann cells. Expression of exogenous neurotrophins by infection with vaccinia virus vector showed that mouse pro-NGF and rat pro-BDNF are cleaved intracellularly on smaller forms of 13.5 kDa NGF and 14 kDa BDNF. Infection experiments demonstrated that Schwann cells contain active processing enzymes. In conclusion, this work provides in vivo evidence of the presence of several PCs in the injured rat sciatic nerve and ex vivo in cultured Schwann cells.
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PMID:The pro-protein convertase PC1 is induced in the transected sciatic nerve and is present in cultured Schwann cells: comparison with PC5, furin and PC7, implication in pro-BDNF processing. 972 4

Propentofylline (Karsivan, Hoechst Roussel Vet) is a selective inhibitor of adenosine transport and phosphodiesterase. For several years it has been well established in the geriatric therapy of the dog improving hemodynamics in cerebral and peripheral compartments. In human medicine clinical development of this pharmaceutical has already entered an advanced stage for the long-term therapy of patients with Alzheimer's disease and vascular dementia. In the brains of senile dogs and in human patients suffering from Alzheimer's disease comparable neuropathological findings can be made. In senile dogs a distinctive correlation exists between the quantity of beta-amyloid accumulation and the degree of dementia. The extension of knowledge by clinical studies in humans and by experimental studies in animals may contribute to a deeper understanding of therapeutical approaches of cognitive dysfunction in the old dog. The xanthine derivative propentofylline [1-(5'-oxohexyl)-3-methyl-7-propylxanthine] directly interfers with the neurodegenerative process and reduces the extent of damage to brain structures. In experimental models of vascular dementia and/or Alzheimer's disease it improves cognitive functions, inhibits inflammatory processes as well as excessive activation of microglia, formation of free radicals, cytocines and abnormal amyloid precursor proteins (APP). It stimulates synthesis and liberation of nerve growth factor (NGF) and reduces ischemic damage to the brain. In clinical studies in humans it improved cognitive functions as well as global functions and the ability to cope with tasks of routine daily life in patients suffering from Alzheimer's disease and vascular dementia.
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PMID:[New pharmacologic aspects in the neurologic profile of propentofylline (Karsivan ad us. vet.)]. 993 90

Apoptotic cell death has been implicated in Alzheimer's disease pathology and amyloid peptide induced neurotoxicity. We investigated the survival promoting effects of Propentofylline in two models of apoptotic cell death, nerve growth factor withdrawal and beta-amyloid mediated cell death in nerve growth factor differentiated rat pheochromocytoma cell lines. The increase in cell death as measured by lactate dehydrogenase release in response to nerve growth factor withdrawal was suppressed by nitric oxide donor S-nitroso-N-acetylpenicillamine (12.5 to 200 microM) and by 8-bromoguanosine-3',5'-cyclic monophosphate (1.25 to 10mM). Both agents decreased cell death mediated by 25 microM beta-amyloid, suggesting that the protective mechanism involves guanosine -3', 5'-cyclic monophosphate. In support of this hypothesis we can show that S-nitroso-N-acetylpenicillamine increases intracellular levels of guanosine -3',5'-cyclic monophosphate in pheochromocytoma cell lines 3 to 8 fold.Propentofylline, a phosphodiesterase inhibitor, has previously demonstrated neuroprotective activity in stroke models and is a potential candidate for therapeutic treatment in neurodegenerative diseases. The present findings support this claim by providing evidence that Propentofylline has protective effects in both nerve growth factor withdrawal and beta-amyloid mediated cell death. Lactate dehydrogenase release was significantly reduced and caspase-3-like activity was attenuated after cotreatment with Propentofylline. Furthermore Propentofylline dose responsively increases intracellular guanosine-3',5'-cyclic monophosphate levels over the same dose range that provided protection. We hypothesized that guanosine-3',5'-cyclic monophosphate is a key mediator of neuroprotection under these conditions.
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PMID:Guanosine 3',5'-cyclic monophosphate mediated inhibition of cell death induced by nerve growth factor withdrawal and beta-amyloid: protective effects of propentofylline. 1097 37

The phosphodiesterase inhibitor, ibudilast, has many effects on lymphocytes, endothelial cells, and glial cells. We examined the neuroprotective role of ibudilast in neuron and microglia co-cultures. Ibudilast significantly suppressed neuronal cell death induced by the activation of microglia with lipopolysaccharide (LPS) and interferon (IFN)-gamma. To examine the mechanisms by which ibudilast exerts a neuroprotective role against the activation of microglia, we examined the production of inflammatory and anti-inflammatory mediators and trophic factors following ibudilast treatment. In a dose-dependent manner, ibudilast suppressed the production of nitric oxide (NO), reactive oxygen species, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha and enhanced the production of the inhibitory cytokine, IL-10, and additional neurotrophic factors, including nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), and neurotrophin (NT)-4 in activated microglia. Thus, ibudilast-mediated neuroprotection was primarily due to the inhibition of inflammatory mediators and the upregulation of neurotrophic factor. In the CA1 region of hippocampal slices, long-term potentiation (LTP) induced by high frequency stimulation (HFS) could be inhibited with LPS and interferon-gamma stimulation. Ibudilast returned this LTP inhibition to the levels observed in controls. These results suggest that ibudilast may be a useful neuroprotective and anti-dementia agent counteracting neurotoxicity in activated microglia.
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PMID:Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia. 1497 96

Key pathological hallmarks of Alzheimer's disease (AD) are the deposition of amyloid plaques containing Abeta-peptides and the formation of neurofibrillary tangles containing hyperphosphorylated tau. Propentofylline (PPF) is a synthetic xanthine derivative that inhibits phosphodiesterase and adenosine uptake. These effects of PPF influence many cellular functions including stimulating synthesis/release of nerve growth factor. We tested the effects of PPF on disease progression in transgenic mice overexpressing the Swedish mutant human APP (Tg2576). The untreated Tg mice show, together with increased amyloidogenesis, increased levels of tau hyperphosphorylation and increased ratios of the activated to inactivated GSK-3beta, one of the key kinases that can phosphorylate tau. One month of PPF feeding (40 mg/kg per day) reduced the burden of amyloid plaques and the levels of hyperphosphorylated tau and immunoreactive IL-1beta. In parallel with these changes, PPF reduced the activated form of GSK-3beta and increased the inactivated form of GSK-3beta, restoring their ratio almost to normal values. These results demonstrate that PPF can exert multiple protective effects on both amyloidogenesis and tau hyperphosphorylation in an animal model of AD. Our earlier report [Neurochem. Int. 43(3) (2003) 225] demonstrated that Tg2576 animals show decreased levels of mRNA for NGF with increased amyloid burden while feeding of PPF results in a major shift from beta-amyloidogenic to alpha-secretory processing of APP together with increased expression of NGF mRNA. The current new data enlarge our understanding of PPF effects in brain and of tau hyperphosphorylation in Tg animals and are consistent with the hypothesis that GSK-3beta is a nodal point linking amyloid and tau pathology. Therapeutic interventions directed toward multiple pathological processes may be more protective than treatments directed toward a single process. The new results reported here indicate that further testing of PPF as a potential therapy in AD is warranted.
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PMID:Propentofylline attenuates tau hyperphosphorylation in Alzheimer's Swedish mutant model Tg2576. 1561 31

Drug-associated vascular injury can be caused by phosphodiesterase (PDE) IV inhibitors and drugs from several other classes. The pathogenesis is poorly understood, but it appears to include vascular and innate immunological components. This research was undertaken to identify changes in peripheral blood associated with vascular injury caused by PDE IV inhibitors. We evaluated twelve proteins, serum nitrite, and leukocyte populations in peripheral blood of rats treated with experimental PDE IV inhibitors. We found that these compounds produced histological microvascular injury in a dose- and time-dependent manner. Measurement of these serum proteins showed changes in eight of the twelve examined. Changes were seen in the levels of: tissue inhibitor of metalloproteinase-1, alpha1-acid glycoprotein, GRO/CINC-1, vascular endothelial growth factor, C-reactive protein, haptoglobin, thrombomodulin, and interleukin-6. No changes were seen in levels of tumor necrosis factor-alpha, hepatocyte growth factor, nerve growth factor, and granulocyte-monocyte colony stimulating factor. Serum levels of nitrite were also increased. Circulating granulocyte numbers were increased, and lymphocyte numbers were decreased. The changes in these parameters showed both a dose- and time-dependent association with histopathologic changes. These biomarkers could provide an additional tool for the nonclinical and clinical evaluation of investigational compounds.
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PMID:Biomarkers in peripheral blood associated with vascular injury in Sprague-Dawley rats treated with the phosphodiesterase IV inhibitors SCH 351591 or SCH 534385. 1877 66


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