Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Donepezil is the current standard symptomatic treatment of mild-to-moderate Alzheimer's disease (AD) patients. It aims to compensate for the deficit in cholinergic neurotransmission by blocking acetylcholinesterase (AChE) and thus increases the concentration of extracellular acetylcholine. However, experience from clinical practice demonstrated that AChE inhibitors only have moderate treatment effects. As a potential new approach for memory enhancement, inhibition of specific phosphodiesterases (PDEs) has gained attention. Among those are PDE9A inhibitors which increase the levels of the second messenger cyclic guanosine monophosphate (cGMP) intracellularly. In order to gain more insight into the potential impact of extracellularly acting AChEs and intracellularly acting PDE9A inhibitors on synaptic plasticity, we analyzed the effects of the AChE inhibitor donepezil and the PDE9A inhibitor BAY 73-6691 on long-term potentiation (LTP) in rat hippocampal slices, a widely accepted cellular experimental model of memory formation. Generally, LTP can be differentiated into an early and a late form, being protein-synthesis independent and protein-synthesis dependent, respectively. Donepezil was found to increase early LTP, but did not affect late LTP. In contrast, BAY 73-6691 demonstrated enhancing effects on both early and late LTP and even transformed early into late LTP. Furthermore, it was shown that this transformation into late LTP was dependent on the NO-cGMP-PKG pathway. In conclusion, this study demonstrates that BAY 73-6691 exhibits a stronger effect in enhancing and prolonging LTP than donepezil suggesting that PDE9 inhibition might be more efficacious in enhancing learning and memory.
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PMID:Inhibition of acetylcholinesterase and phosphodiesterase-9A has differential effects on hippocampal early and late LTP. 2224 62

The number of patients with heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF) is increasing, and for HFpEF, no therapies have clinical benefit. It has been hypothesized that PKG attenuates pathological remodelling, and increasing cGMP would be beneficial for patients with HF. However, neither the RELAX nor NEAT-HFpEF trial showed benefit. But there is still enthusiasm for increasing cGMP in patients with HF, which highlight the need to determine the expression of PDEs in cardiac muscle. This study used immunoblotting to examine the expression of the PDEs that have been suggested to be targets for therapy of HF in both canines (normal and HFpEF) and humans (normal and HFrEF). Our results demonstrate PDE1C and PDE3A are expressed in cardiac muscle, but we could not detect the expression of PDE2A, PDE5A, PDE7A and PDE9A in cardiac tissue lysates from either normal or failing hearts. Thus, one should not expect a clinical benefit for a therapy targeting these PDEs in heart failure, which highlights the importance of rigorous demonstration of the target of therapy prior to undertaking a clinical trial.
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PMID:Phosphodiesterase expression in the normal and failing heart. 3055 Jul 27