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)

Previous evidences reported by us and by other authors revealed the presence of IgG in sera of Schistosoma mansoni-infected patients to immunodominant antigens which are enzymes. Besides their immunological interest as possible inductors of protection, several of these enzyme antigens might be also interesting markers of infection in antibody-detecting immunocapture assays which use the intrinsic catalytic property of these antigens. It was thus thought important to define some enzymatic and immunological characteristics of these molecules to better exploit their use as antigens. Four different enzymes from adult worms were partially characterized in their biochemical properties and susceptibility to react with antibodies of infected patients, namely alkaline phosphatase (AKP, Mg2+, pH 9.5), type I phosphodiesterase (PDE, pH 9.5), cysteine proteinase (CP, dithiothreitol, pH 5.5) and N-acetyl-beta-D-glucosaminidase (NAG, pH 5.5). The AKP and PDE are distinct tegumental membrane-bound enzymes whereas CP and NAG are soluble acid enzymes. Antibodies in infected human sera differed in their capacity to react with and to inhibit these enzyme antigens. Possibly, the specificity of the antibodies related to the extent of homology between the parasite and the host enzyme might be in part responsible for the above differences. The results are also discussed in view of the possible functional importance of these enzymes.
Mem Inst Oswaldo Cruz 1992
PMID:Parasite enzymes as a tool to investigate immune responses. 134 26

The elevation of intracellular cyclic AMP by phosphodiesterase (PDE)4 inhibitors in eosinophils is associated with inhibition of the activation and recruitment of these cells. We have previously shown that systemic treatment with the PDE4 inhibitor rolipram effectively inhibit eosinophil migration in guinea pig skin. In the present study we compare the oral potency and efficacy of the PDE4 inhibitors rolipram, RP 73401 and CDP 840 on allergic and PAF-induced eosinophil recruitment. Rolipram and RP 73401 were equally effective and potent when given by the oral route and much more active than the PDE4 inhibitor CDP 840. We suggest that this guinea pig model of allergic and mediator-induced eosinophil recruitment is both a sensitive and simple tool to test the efficacy and potency of PDE4 inhibitors in vivo.
Mem Inst Oswaldo Cruz 1997
PMID:A comparison of the inhibitory activity of selective PDE4 inhibitors on eosinophil recruitment in guinea pig skin. 969 32

In the present study, we have performed a comparative analysis of the effect of selective inhibitors of phosphodiesterase (PDE) type III, IV and V on eosinophil chemotaxis triggered by platelet activating factor (PAF) and leukotriene B4 (LTB4) in vitro. The effect of the analogues N6-2'-O-dibutyryladenosine 3':5'cyclic monophosphate (Bt2 cyclic AMP) and N2-2'-O-dibutyrylguanosine 3':5' cyclic monophosphate (Bt2 cyclic GMP) has also been determined. The eosinophils were obtained from the peritoneal cavity of naive Wistar rats and purified in discontinuous Percoll gradients to 85-95% purity. We observed that pre-incubation of eosinophils with the PDE type IV inhibitor rolipram suppressed the chemotactic response triggered by PAF and LTB4' in association with an increase in the intracellular levels of cyclic AMP. In contrast, neither zaprinast (type V inhibitor) nor type III inhibitors milrinone and SK&F 94836 affected the eosinophil migration. Only at the highest concentration tested did the analogue Bt2 cyclic AMP suppress the eosinophil chemotaxis, under conditions where Bt2 cyclic GMP was ineffective. We have concluded that inhibition of PDE IV, but not PDE III or V, was able to block the eosinophil chemotaxis in vitro, suggesting that the suppressive activity of selective PDE IV inhibitors on tissue eosinophil accumulation may, at least, be partially dependent on their ability to directly inhibit the eosinophil migration.
Mem Inst Oswaldo Cruz 1997
PMID:Effect of selective phosphodiesterase inhibitors on the rat eosinophil chemotactic response in vitro. 969 34

The role of cyclic nucleotides in the transduction of the hyperprolinaemic and hypertrehalosaemic signal of the endogenous neuropeptide Mem-CC was investigated in the cetoniid beetle Pachnoda sinuata. Flight and injection of Mem-CC into the haemocoel of the beetle induce an increase of cAMP levels in the fat body of the beetle. This increase is tissue-specific and does not occur in brain and flight muscles. An elevation of cAMP levels was also found when in vitro preparations of fat body tissue were subjected to Mem-CC. Elevation of the cAMP concentration after injection of Mem-CC is time- and dose-dependent: the maximum response is measured after 1 min, and a dose of 25 pmol Mem-CC is needed. Injection of cpt-cAMP, a cAMP analogue which penetrates the cell membrane, causes a stimulation of proline synthesis but no mobilisation of carbohydrate reserves. The same is measured when IBMX, an inhibitor of phosphodiesterase, is injected. cGMP seems not to be involved in synthesis of proline nor carbohydrate release, because injection of cpt-cGMP has no influence on the levels of proline, alanine and carbohydrates in the haemolymph. Although glycogen phosphorylase of the fat body is activated by Mem-CC in a time- and dose-dependent manner, it cannot be stimulated by cpt-cAMP. The combined data suggest that cAMP is involved in regulation of proline levels by Mem-CC but not in regulation of carbohydrates. Octopamine has no effect on metabolites in the haemolymph and is not capable of activating glycogen phosphorylase, indicating that it is not involved in the regulation of substrates in this beetle. Furthermore, the requirements of the receptor of Mem-CC are different for eliciting a hypertrehalosaemic and a hyperprolinaemic effect, respectively, suggesting that differentiation in signal transduction begins at the receptor level.
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PMID:Cyclic AMP mediates the elevation of proline by AKH peptides in the cetoniid beetle, Pachnoda sinuata. 1063 34

As many metalloproteinases (MMPs), macrophage elastase (MMP-12) is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling processes. Studies using animal models of acute and chronic pulmonary inflammatory diseases, such as pulmonary fibrosis and chronic obstructive pulmonary disease (COPD), have given evidences that MMP-12 is an important mediator of the pathogenesis of these diseases. However, as very few data regarding the direct involvement of MMP-12 in inflammatory process in the airways were available, we have instilled a recombinant form of human MMP-12 (rhMMP-12) in mouse airways. Hence, we have demonstrated that this instillation induced a severe inflammatory cell recruitment characterized by an early accumulation of neutrophils correlated with an increase in proinflammatory cytokines and in gelatinases and then by a relatively stable recruitment of macrophages in the lungs over a period of ten days. Another recent study suggests that resident alveolar macrophages and recruited neutrophils are not involved in the delayed macrophage recruitment. However, epithelial cells could be one of the main targets of rhMMP-12 in our model. We have also reported that a corticoid, dexamethasone, phosphodiesterase 4 inhibitor, rolipram and a non-selective MMP inhibitor, marimastat could reverse some of these inflammatory events. These data indicate that our rhMMP-12 model could mimic some of the inflammatory features observed in COPD patients and could be used for the pharmacological evaluation of new anti-inflammatory treatment. In this review, data demonstrating the involvement of MMP-12 in the pathogenesis of pulmonary fibrosis and COPD as well as our data showing a pro-inflammatory role for MMP-12 in mouse airways will be summarized.
Mem Inst Oswaldo Cruz 2005 Mar
PMID:Macrophage elastase (MMP-12): a pro-inflammatory mediator? 1596 17

In this study, the effect of the selective phosphodiesterase type 4 (PDE4) inhibitor rolipram on memory performance was investigated using the object recognition task. First, three doses of rolipram (0.01, 0.03 or 0.1 mg/kg) were tested with a 24h delay between the learning (T1) and the test (T2) trial. Doses of rolipram were injected at different time points (30 min before T1, immediately after T1 or 3 h after T1). In a second experiment, the effects of rolipram (0.03, 0.1 or 0.3 mg/kg) were tested in combination with scopolamine (0.1 mg/kg) applying a 1 h delay between trials. Both substances were administered 30 min before T1. Using a 24h interval, rolipram showed an improvement in long-term memory performance when injected 3 h after T1 at a dose of 0.03 mg/kg. Further, rolipram reversed the scopolamine-induced short-term memory deficit at a dose of 0.1 mg/kg. Although the improved memory performance in both conditions is likely to be explained by elevated cAMP levels, two separate working mechanisms might explain these effects.
Neurobiol Learn Mem 2006 Mar
PMID:Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action. 1624 77

The working-memory functions of the prefrontal cortex (PFC) are improved by stimulation of postsynaptic, alpha2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the alpha2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and rats following systemic administration or intra-PFC infusion. Alpha2A-adrenoceptors are generally coupled to Gi, which can inhibit adenylyl cyclases and reduce the production of cAMP. However, no study has directly examined whether the working-memory enhancement observed with guanfacine or other alpha2A-adrenoceptor agonists results from cAMP inhibition. The current study confirmed this hypothesis in both rats and monkeys, showing that treatments that increase cAMP-mediated signaling block guanfacine's beneficial effects. In aged rats, guanfacine was infused directly into the prelimbic PFC and was challenged with co-infusions of the cAMP analog, Sp-cAMPS. In aging monkeys, systemically administered guanfacine was challenged with the phosphodiesterase 4 inhibitor, rolipram, using intramuscular doses known to have no effect on their own. In both studies, agents that mimicked the actions of cAMP (rats) or increased endogenous cAMP (monkeys) completely blocked the enhancing effects of guanfacine on working-memory performance. These results are consistent with alpha2A-adrenoceptor stimulation enhancing PFC working-memory function via inhibition of cAMP-mediated signaling.
Learn Mem
PMID:Alpha2A-adrenoceptor stimulation improves prefrontal cortical regulation of behavior through inhibition of cAMP signaling in aging animals. 1710 79

The cAMP/PKA pathway plays a critical role in learning and memory systems in animals ranging from mice to Drosophila to Aplysia. Studies of olfactory learning in Drosophila suggest that altered expression of either positive or negative regulators of the cAMP/PKA signaling pathway beyond a certain optimum range may be deleterious. Here we provide genetic evidence of the behavioral and physiological effects of increased signaling through the cAMP/PKA pathway in mice. We have generated transgenic mice in which the expression of a constitutively active form of Gsalpha (Gsalpha* Q227L), the G protein that stimulates adenylyl cyclase activity, is driven in neurons within the forebrain by the promoter from the CaMKIIalpha gene. Despite significantly increased adenylyl cyclase activity, Gsalpha* transgenic mice exhibit PKA-dependent decreases in levels of cAMP due to a compensatory up-regulation in phosphodiesterase activity. Interestingly, Gsalpha* transgenic mice also exhibit enhanced basal synaptic transmission. Consistent with a role for the cAMP/PKA pathway in learning and memory, Gsalpha* transgenic mice show impairments in spatial learning in the Morris water maze and in contextual and cued fear conditioning tasks. The learning deficits observed in these transgenic mice suggest that associative and spatial learning requires regulated Gsalpha protein signaling, much as does olfactory learning in Drosophila.
Learn Mem
PMID:Chronically increased Gsalpha signaling disrupts associative and spatial learning. 1714 4

Memory formation requires cAMP signaling; thus, this cascade has been of great interest in the search for cognitive enhancers. Given that medications are administered long-term, we determined the effects of chronically increasing cAMP synthesis in the brain by expressing a constitutively active isoform of the G-protein subunit Galphas (Galphas*) in postnatal forebrain neurons of mice. Previously, we showed that Galphas* mice exhibit increased adenylyl cyclase activity but decreased cAMP levels in cortex and hippocampus due to a PKA-dependent increase in total cAMP phosphodiesterase (PDE) activity. Here, we extend previous findings by determining if Galphas* mice show increased activity of specific PDE families that are regulated by PKA, if Galphas* mice show PKA-dependent deficits in fear memory, and if these memory deficits are associated with PKA-dependent alterations in neuronal activity as mapped by Arc mRNA expression. Consistent with previous findings, we show here that Galphas* mice exhibit a significant compensatory increase in cAMP PDE1 activity and a trend toward increased cAMP PDE4 activity. Further, inhibiting the presumably elevated PKA activity in Galphas* mice fully rescues short- and long-term memory deficits in a fear-conditioning task, while extending the training session from one to four CS-US pairings partially rescues these deficits. Mapping of Arc mRNA levels suggests these PKA-dependent memory deficits may be related to decreased neuronal activity specifically within the cortex. Galphas* mice show decreased Arc mRNA expression in CA1, orbital cortex, and cortical regions surrounding the hippocampus; however, only the deficits in cortical regions surrounding the hippocampus are PKA dependent. Our results imply that chronically stimulating targets upstream of cAMP may detrimentally affect cognition.
Learn Mem 2008 Feb
PMID:Constitutive activation of the G-protein subunit Galphas within forebrain neurons causes PKA-dependent alterations in fear conditioning and cortical Arc mRNA expression. 1823 Jun 76

Cyclic AMP signaling plays a central role in regulating activity at a number of synapses in the brain. We showed previously that pairing activation of receptors that inhibit adenylate cyclase (AC) and reduce the concentration of cyclic AMP, with elevation of the concentration of cyclic GMP is sufficient to elicit a presynaptically expressed form of LTD at Schaffer collateral-CA1 synapses in the hippocampus. To directly test the role of AC inhibition and G-protein signaling in LTD at these synapses, we utilized transgenic mice that express a mutant, constitutively active inhibitory G protein, Galpha(i2), in principal neurons of the forebrain. Transgene expression of Galpha(i2) markedly enhanced LTD and impaired late-phase LTP at Schaffer collateral synapses, with no associated differences in input/output relations, paired-pulse facilitation, or NMDA receptor-gated conductances. When paired with application of a type V phosphodiesterase inhibitor to elevate the concentration of intracellular cyclic GMP, constitutively active Galpha(i2) expression converted the transient depression normally caused by this treatment to an LTD that persisted after the drug was washed out. Moreover, this effect could be mimicked in control slices by pairing type V phosphodiesterase inhibitor application with application of a PKA inhibitor. Electrophysiological recordings of spontaneous excitatory postsynaptic currents and two-photon visualization of vesicular release using FM1-43 revealed that constitutively active Galpha(i2) tonically reduced basal release probability from the rapidly recycling vesicle pool of Schaffer collateral terminals. Our findings support the hypothesis that inhibitory G-protein signaling acts presynaptically to regulate release, and, when paired with elevations in the concentration of cyclic GMP, converts a transient cyclic GMP-induced depression into a long-lasting decrease in release.
Learn Mem 2008 Apr
PMID:Galpha(i2) inhibition of adenylate cyclase regulates presynaptic activity and unmasks cGMP-dependent long-term depression at Schaffer collateral-CA1 hippocampal synapses. 1839 Nov 87


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