Phosphodiesterases and Cyclic Nucleotide Signaling In The CNS

Conti, Marco; Richter, Wito

doi:10.1002/9781118836507.ch01

Cited by 3 publications

(3 citation statements)

References 256 publications

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“…PDE1 is a member of the group of PDEs responsible for the hydrolysis of phosphodiester bonds during cAMP breakdown. This enzyme is abundantly found in several cognition-related regions of the brain, such as the hippocampus [14,27,28].…”

Section: Discussionmentioning

confidence: 99%

“…Several lines of evidence indicate that phosphodiesterase (PDE), the enzyme responsible for the hydrolytic breakdown of cyclic nucleotides (e.g., cAMP/cGMP), is a potential molecular target in AD. Inhibition of PDE activity can increase cyclic nucleotide levels in the brain, which is important to activate brain synaptic protein expression pathways for learning and memory maintenance [13,14]. Vinpocetine and rolipram, two PDE inhibitors currently used to treat AD, have shown great promise in efforts to address the degenerative features of the disease.…”

Section: Introductionmentioning

confidence: 99%

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Caesalpinia sappan L. Ameliorates Scopolamine-Induced Memory Deficits in Mice via the cAMP/PKA/CREB/BDNF Pathway

et al. 2021

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Memory is an essential aspect of human cognition. A decrease in this aspect is well associated with Alzheimer’s disease (AD). The development of a novel cognitive enhancer (CE) may help overcome AD-related problems. In this study, we evaluated the CE effect of Caesalpinia sappan L. (CS) in memory deficit mice. Administration of its ethanolic extract (250 and 500 mg/kg body weight (BW)) and brazilin (5 and 10 mg/kg BW) ameliorated the scopolamine-amnesic effect, as evidenced by significant decreases (p < 0.01, p < 0.05) in the escape latency time and increases (p < 0.01) in the percentage of time spent in the target quadrant of the Morris water maze test. We also examined the cyclic adenosine monophosphate (cAMP) level, protein kinase A (PKA) activity, and protein expression levels of phosphorylated cAMP response element binding (pCREB) and brain-derived neurotrophic factor (BDNF) in hippocampal tissues to elucidate the underlying molecular mechanism. Results showed that CS wood ethanolic extract and brazilin not only significantly increase (p < 0.01, p < 0.05) cAMP levels and PKA activity but also significantly enhance (p < 0.01, p < 0.05) the expression level of pCREB and BDNF in the hippocampus. These findings indicate that CS activates the cAMP/PKA/CREB/BDNF pathway. Taken together, our results demonstrate that CS is a promising herb that could be developed as a CE agent.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Caesalpinia sappan L. Ameliorates Scopolamine-Induced Memory Deficits in Mice via the cAMP/PKA/CREB/BDNF Pathway

et al. 2021

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“…cGMP, on the other hand, relays signals from nitric oxide to activate protein kinase G (PKG). Phosphodiesterase (PDE), the enzyme that degrades cGMP, can be a cGMP effector with its activity modulated by cGMP binding to regulatory domains forming feedback loops (Conti and Richter, 2014 ). Both cyclic nucleotides also activate cyclic nucleotide gated ion channels (Rich et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Visualization of cyclic nucleotide dynamics in neurons

Gorshkov

Zhang

2014

Front. Cell. Neurosci.

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The second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) transduce many neuromodulatory signals from hormones and neurotransmitters into specific functional outputs. Their production, degradation and signaling are spatiotemporally regulated to achieve high specificity in signal transduction. The development of genetically encodable fluorescent biosensors has provided researchers with useful tools to study these versatile second messengers and their downstream effectors with unparalleled spatial and temporal resolution in cultured cells and living animals. In this review, we introduce the general design of these fluorescent biosensors and describe several of them in more detail. Then we discuss a few examples of using cyclic nucleotide fluorescent biosensors to study regulation of neuronal function and finish with a discussion of advances in the field. Although there has been significant progress made in understanding how the specific signaling of cyclic nucleotide second messengers is achieved, the mechanistic details in complex cell types like neurons are only just beginning to surface. Current and future fluorescent protein reporters will be essential to elucidate the role of cyclic nucleotide signaling dynamics in the functions of individual neurons and their networks.

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Target Engagement of a Phosphodiesterase 2A Inhibitor Affecting Long-Term Memory in the Rat

Scott

Yan

et al. 2019

J Pharmacol Exp Ther

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Inhibition of phosphodiesterase 2A (PDE2A) has been proposed as a potential approach to enhance cognitive functioning and memory through boosting intracellular cGMP/cAMP and enhancing neuroplasticity in memory-related neural circuitry. Previous preclinical studies demonstrated that PDE2A inhibitors could reverse N-methyl-D-aspartate receptor antagonist (5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10imine or ketamine-induced memory deficit. Here, we report that the potent and selective PDE2A inhibitor 4-(1-azetidinyl)-7-methyl-5-[1-methyl-5-[5-(trifluoromethyl)-2-pyridinyl]-1H-pyrazol-4-yl]imidazo[5,1-f][1,2,4]triazine (PF-05180999) enhances long-term memory in a contextual fear conditioning model in the rat at the oral dose of 0.3 mg/kg. Target engagement at this efficacious dose was explored using in vivo autoradiography. Converse to the results of a decrease of PDE2A binding (target occupancy) by the PDE2A inhibitor, a paradoxical increase (up to 40%) in PDE2A binding was detected. However, a typical target occupancy curve could be generated by PF-05180999 at much higher doses. In vitro experiments using recombinant PDE2A protein or rat brain homogenate that contains native PDE2A protein demonstrated that increased cGMP after initial PDE2A inhibition could be responsible for the activation of PDE2A enzyme via allosteric binding to the GAF-B domain, leading to positive cooperativity of the dormant PDE2A enzymes. Our results suggest that when evaluating target engagement of PDE2A inhibitors for memory disorder in clinical setting with occupancy assays, the efficacious dose may not fall on the typical receptor/target curve. On the contrary, an increase in PDE2A tracer binding is likely seen. Our results also suggest that when evaluating target occupancy of enzymes, potential regulation of enzyme activities should be considered.

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Phosphodiesterases and Cyclic Nucleotide Signaling In The CNS

Cited by 3 publications

References 256 publications

Caesalpinia sappan L. Ameliorates Scopolamine-Induced Memory Deficits in Mice via the cAMP/PKA/CREB/BDNF Pathway

Caesalpinia sappan L. Ameliorates Scopolamine-Induced Memory Deficits in Mice via the cAMP/PKA/CREB/BDNF Pathway

Visualization of cyclic nucleotide dynamics in neurons

Target Engagement of a Phosphodiesterase 2A Inhibitor Affecting Long-Term Memory in the Rat

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