Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP

Kroker, Katja S.; Rast, Georg; Giovannini, Riccardo; Marti, Anelise; Dorner-Ciossek, Cornelia; Rosenbrock, Holger

doi:10.1016/j.neuropharm.2011.12.021

Cited by 55 publications

(51 citation statements)

References 114 publications

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“…Devan et al (2007) blocked cGMP-PKG signaling in vivo through upstream inhibition of nitric oxide synthase, and could attenuate subsequent memory impairment with a PDE5 inhibitor. In accordance with our present findings, Kroker et al (2012) were able to convert E-LTP into L-LTP by increasing cGMP via a PDE9 inhibitor, which was blocked by co-application with a PKG inhibitor. Moreover, our results now show that for cAMP as well as cGMP stimulation, the subsequent activation of their respective PKs is required for the memory-enhancing effects of PDE inhibition.…”

Section: Discussionsupporting

confidence: 93%

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Bollen

Puzzo

Rutten

et al. 2014

Neuropsychopharmacol

102

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Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long-lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/protein kinase G (PKG) signaling mediates early memory consolidation as well as early-phase LTP, whereas cAMP/protein kinase A (PKA) signaling mediates late consolidation and late-phase-like LTP. In addition, we show for the first time that early-phase cGMP/PKG signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation.

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Section: Discussionsupporting

confidence: 93%

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Bollen

Puzzo

Rutten

et al. 2014

Neuropsychopharmacol

102

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“…25,28 This suggests that the potential side effects of drugs inhibiting either enzymes, are probably very different. PDE9 inhibitors are currently undergoing clinical trials (eg, NCT00930059 and NCT00736528) for potential use in the treatment of Alzheimer disease, because they have been shown to improve cognition and memory 48,49 ; although no data are currently available regarding the side effects of these drugs.…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

Almeida

Scheiermann

Jang

et al. 2012

Blood

116

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Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-␣-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobinelevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease. (Blood. 2012;120(14): 2879-2888) IntroductionSickle cell disease (SCD) is a genetic disorder caused by a point mutation in the HBB gene, resulting in the production of abnormal sickle hemoglobin (HbS). 1,2 HbS polymerizes at low oxygen levels, making the red blood cell (RBC) more rigid and, eventually, irreversibly sickled. This causes the complex pathophysiology of SCD that includes hemolysis, chronic inflammation, elevated cell adhesion, leukocytosis, increased oxidative stress, and endothelial activation/dysfunction, which can culminate in the acute vasoocclusive processes that are responsible for much of the morbidity observed in patients. 1,2 Vaso-occlusion comprises multistep and multicellular processes that appear to be initiated by the adhesion of red cells and leukocytes to activated endothelium via a mechanism in which inflammation, hypoxic events, oxidative stress, and reduced nitric oxide availability probably play roles. [3][4][5][6][7] Data from in vivo studies using SCD mice 5,8,9 and in vitro studies 10 indicate that the recruitment of large, less deformable leukocytes to the vessel wall, and their subsequent interactions with circulating RBCs, may initiate vaso-occlusion. As such, drugs that inhibit the adhesion of leukocytes to vascular endothelium may represent an important approach for decreasing, or even preventing, vaso-occlusion. 11 Research over recent years indicates that reduced nitric oxide (NO) bioavailability may contribute to manifestations of SCD, such as pulmonary hypertension and cutaneous leg ulceration. 12,13 Whether reduced NO signaling has a direct role in the vasoocclusi...

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“…A comparative analysis of the effects of family-specific PDE inhibitors on different aspects of synaptic transmission that culminate in LTP would be extremely valuable. There is now emerging data on the effects of PDE inhibitors on the regulation of phosphorylation of downstream targets related to synaptic plasticity that may begin to provide insight into differentiation [23]. However, there is surprisingly little information in CNS tissues linking specific PDEs to upstream cyclase activator cascades.…”

Section: Functional Effects Of Pde Inhibitorsmentioning

confidence: 99%

PDE Inhibition and cognition enhancement

Blokland¹,

Menniti

Prickaerts

2012

Expert Opinion on Therapeutic Patents

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Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP

Cited by 55 publications

References 114 publications

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice

PDE Inhibition and cognition enhancement

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