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)

We investigated the age-related alterations of astorocyte, oligodendrocyte and microglia in the mouse hippocampal CA1 sector under the same conditions using immunohistochemistry. Glial fibrillary acidic protein (GFAP), 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) and isolectin B(4) immunoreactivity was measured in 2-, 8-, 18-, 40-42- and 50-59-week-old mice. Total number of GFAP-positive cells was unchanged in the hippocampal CA1 sector up to 40-42 weeks of birth. In 50-59-week-old mice, however, a significant increase in the number of GFAP-positive cells was observed in the hippocampal CA1 sector, exhibiting the morphology of reactive astrocytes. In contrast, the fibers of CNPase immunoreactivity were unchanged in the hippocampal CA1 sector up to 18 weeks of birth. In 40-42- and 50-59-week-old mice, however, a significant decrease in the densities of CNPase-positive fibers was observed in the hippocampal CA1 sector. On the other hand, total number of isolectin B(4)-positive cells was unchanged in the hippocampal CA1 sector up to 40-42 weeks of birth. In 50-59-week-old mice, however, a significant decrease in the number of isolectin B(4)-positive cells was observed in the hippocampal CA1 sector. Our results show that astrocytes proliferate and are activated in the hippocampal CA1 sector with advancing age. Furthermore, the present study demonstrates that the fibers of oligodendrocytes and total number of microglial cells in the hippocampal CA1 sector are decreased during ageing processes. These results suggest that age-related changes of astorocytes, oligodendrocytes and microglia had occurred in the mouse hippocampal CA1 sector.
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PMID:Age-related changes of astorocytes, oligodendrocytes and microglia in the mouse hippocampal CA1 sector. 1735 Jun 71

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.
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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.
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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

A role for guanosine 3',5'-cyclic monophosphate (cGMP) and the protein kinase G (PKG) pathway in synaptic long-term depression (LTD) in the hippocampal CA1 region has been proposed, based on observations in vitro, where, for example, increases of [cGMP] result in short-term depression (STD) coupled with a reduction in presynaptic glutamate release. To date, no evidence exists to support that LTD in the intact, freely behaving animal involves these mechanisms. We examined the effect of increases of [cGMP] on basal transmission and electrically-induced STD at hippocampal CA1 synapses in vivo. We found that elevating [cGMP] dose-dependently caused a chemically-induced STD which occluded electrically-induced STD. Repeated administration of Zaprinast, an inhibitor of cGMP-degrading phosphodiesterase, resulted in persistent LTD (>24 h). Paired-pulse analysis supported a presynaptic mechanism of action. Application of an inhibitor of soluble guanylate cyclase prevented LTD induced by low-frequency stimulation (LFS), and impaired LFS-STD elicited in the presence of Zaprinast. These data suggest the involvement of cGMP in LTD in the CA1 region of freely behaving adult rats.
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PMID:Regulation of long-term depression by increases in [guanosine 3',5'-cyclic monophosphate] in the hippocampal CA1 region of freely behaving rats. 1847 42

Elevation of intracellular cyclic adenosine monophosphate (cAMP) concentrations and subsequent regulation of downstream target gene expression through phosphorylation of cAMP-responsive element binding protein (CREB) is hypothesized to underlie the mechanism(s) of long-term memory (LTM) formation. The phosphodiesterase 4 (PDE4) enzyme family is believed to play a key role in LTM by regulating cAMP levels. Thus far, four PDE4 isoforms have been identified (PDE4A, B, C and D); however, the requisite involvement of each of these isoforms in mediating LTM has yet to be elucidated. In the present study, genetic knockout mice were used to investigate the involvement of the PDE4D isoform in both in vitro and in vivo models of learning and memory. Hippocampal synaptic transmission measured electrophysiologically in CA1 slice preparations was similar between wild-type and PDE4D (-/-) mice yet, relative to wild-type controls, knockout mice displayed enhanced early long-term potentiation (LTP) following multiple induction protocols. Interestingly, the PDE4D (-/-) animals exhibited significant behavioral deficits in associative learning using a conditioned fear paradigm as compared with control littermates. The impairment in fear conditioning observed in the PDE4D (-/-) mice could not be attributed to differences in acquisition of the task, alterations in locomotor activity or effects on shock sensitivity. Overall, the in vitro and in vivo alterations in synaptic plasticity observed in the PDE4D (-/-) mice may be explained by adaptive responses occurring throughout development, and suggest that the PDE4D isoform may be an important mediator of LTM formation.
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PMID:Enhanced long-term potentiation and impaired learning in phosphodiesterase 4D-knockout (PDE4D) mice. 1870 34

Cerebral ischemia resulting from transient or permanent cerebral artery occlusion leads to neuronal cell death, and eventually causes neurological impairments. Tadalafil (Cialis)is a long-acting phosphodiesterase type-5 (PDE-5) inhibitor used to treat erectile dysfunction. The therapeutic effects of PDE-5 inhibitors on chronic obstructive pulmonary disease, prostate hyperplasia, hypertension, and coronary heart disease have been reported. The present study investigated the effects of tadalafil on short-term memory, cyclic guanosine monophosphate (cGMP) level, apoptotic neuronal cell death, and cell proliferation in the hippocampus following transient global ischemia in gerbils. For this study, a step-down avoidance task, cGMP assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, and immunohistochemistry for caspase-3 and 5-bromo-2'-deoxyuridine were performed. The results revealed that ischemic injury increased apoptotic neuronal cell death in the hippocampal CA1 region, impaired short-term memory, and decreased cGMP level. Ischemic injury enhanced cell proliferation in the hippocampal dentate gyrus. Tadalafil treatment improved short-term memory by suppressing ischemia-induced apoptotic neuronal cell death in the hippocampal CA1 region, and decreased cGMP level. Also, tadalafil suppressed the ischemia-induced increase in cell proliferation in the hippocampal dentate gyrus. We showed that tadalafil can overcome ischemia-induced apoptotic neuronal cell death, thus facilitates recovery following ischemic cerebral injury.
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PMID:Tadalafil improves short-term memory by suppressing ischemia-induced apoptosis of hippocampal neuronal cells in gerbils. 1901 Mar 46

Sildenafil citrate, a phosphodiesterase-5 (PDE5) inhibitor widely used for the treatment of erectile dysfunction was investigated for its interaction with the zinc-enzyme carbonic anhydrase (CA, EC 4.2.1.1), as it has in its molecule a piperazine moiety also found in some CA activators (CAAs). Sildenafil was a potent, low micromolar activator of several CA isozymes, such as CA I, VA and VI (K(A)s in the range of 1.08-6.54microM), and activated slightly less the isoforms CA III, IV and VA (K(A)s of 13.4-16.8microM). CA isozymes II, IX, XIII and XIV showed activation constants in the range of 27.5-34.0microM, whereas the least activated isoforms were CA VII and XII (K(A)s of 72.9-73.0microM). Sildenafil citrate was also given orally to Sprague-Dawley rats at 1mg/kg body weight. Red blood cell CA activity was inhibited in the treated animals at 3-5h post-administration (in the range of 60-85%), probably due to NO/nitrite formed by PDE5 inhibition or by another, unknown mechanism. Whether CA activation by sildenafil has clinical consequences in humans is beyond the scope of the present work and warrants further studies.
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PMID:Sildenafil is a strong activator of mammalian carbonic anhydrase isoforms I-XIV. 1963 71

Cilostazol is known to be a specific type III phosphodiesterase inhibitor, which promotes increased intracellular cAMP levels. We assessed the effect of cilostazol on production of angioneurins and chemokines and recruitment of new endothelial cells for vasculogenesis in a mouse model of transient forebrain ischemia. Pyramidal cell loss was prominently evident 3-28 days postischemia, which was markedly ameliorated by cilostazol treatment. Expression of angioneurins, including endothelial nitric oxide synthase, vascular endothelial growth factor, and brain-derived neurotrophic factor, was up-regulated by cilostazol treatment in the postischemic hippocampus. Cilostazol also increased Sca-1/vascular endothelial growth factor receptor-2 positive cells in the bone marrow and circulating peripheral blood and the number of stromal cell-derived factor-1alpha-positive cells in the molecular layer of the hippocampus, which colocalized with CD31. CXCR4 chemokine receptors were up-regulated by cilostazol in mouse bone marrow-derived endothelial progenitor cells, suggesting that cilostazol may be important in targeting or homing in of bone marrow-derived stem cells to areas of injured tissues. CD31-positive cells were colocalized with almost all bromodeoxyuridine-positive cells in the molecular layer, indicating stimulation of endothelial cell proliferation by cilostazol. These data suggest that cilostazol markedly enhances neovascularization in the hippocampus CA1 area in a mouse model of transient forebrain ischemia, providing a beneficial interface in which both bone marrow-derived endothelial progenitor cells and angioneurins influence neurogenesis in injured tissue. (c) 2010 Wiley-Liss, Inc.
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PMID:Cilostazol enhances neovascularization in the mouse hippocampus after transient forebrain ischemia. 2017 1

The mossy fiber synapses onto hippocampal CA3 neurons show unique molecular features and a wide dynamic range of plasticity. Although acute stress has been well recognized to alter bidirectional long-term synaptic plasticity in the hippocampal CA1 region and dentate gyrus, it remains unclear whether the same effect may also occur at the mossy fiber-CA3 synapses. Here, we report that hippocampal slices prepared from adult mice that had experienced an acute unpredictable and inescapable restraint tail-shock stress showed a marked impairment of long-term potentiation (LTP) induced by high-frequency stimulation or adenylyl cyclase activator forskolin. This effect was prevented when animals were submitted to bilateral adrenalectomy or given the glucocorticoid receptor antagonist RU38486 before experiencing stress. In contrast, stress has no effect on synaptic potentiation induced by the non-hydrolysable and membrane-permeable cyclic adenosine 5'-monophosphate (cAMP) analog Sp-8-bromo-cAMPS. No obvious differences were observed between control and stressed mice in the basal synaptic transmission, paired-pulse facilitation, or frequency facilitation at the mossy fiber-CA3 synapses. We also found that the inhibitory effect of stress on mossy fiber LTP was obviated by the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3,-dipropylxanthine, the non-specific phosphodiesterase (PDE) inhibitor 3-isobutyl-methylxanthine, and the specific PDE4 inhibitor 4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone. In addition, stress induces a sustained and profound increase in cAMP-specific PDE4 activity. These results suggest that the inhibition of mossy fiber LTP by acute stress treatment seems originating from a corticosterone-induced sustained increase in the PDE4 activity to accelerate the metabolism of cAMP to adenosine, in turn triggering an adenosine A(1) receptor-mediated impairment of transmitter release machinery.
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PMID:Acute stress impairs hippocampal mossy fiber-CA3 long-term potentiation by enhancing cAMP-specific phosphodiesterase 4 activity. 2023 61

Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A(-/-) knockout (KO) mice. We show that PDE11A mRNA and protein are largely restricted to hippocampus CA1, subiculum, and the amygdalohippocampal area, with a two- to threefold enrichment in the ventral vs. dorsal hippocampus, equal distribution between cytosolic and membrane fractions, and increasing levels of protein expression from postnatal day 7 through adulthood. Interestingly, PDE11A KO mice show subtle psychiatric-disease-related deficits, including hyperactivity in an open field, increased sensitivity to the glutamate N-methyl-D-aspartate receptor antagonist MK-801, as well as deficits in social behaviors (social odor recognition memory and social avoidance). In addition, PDE11A KO mice show enlarged lateral ventricles and increased activity in CA1 (as per increased Arc mRNA), phenotypes associated with psychiatric disease. The increased sensitivity to MK-801 exhibited by PDE11A KO mice may be explained by the biochemical dysregulation observed around the glutamate alpha-amino-3-hydroxy-5-methyl-4-isozazolepropionic (AMPA) receptor, including decreased levels of phosphorylated-GluR1 at Ser845 and the prototypical transmembrane AMPA-receptor-associated proteins stargazin (gamma2) and gamma8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.
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PMID:Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes. 2040 72


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