Dart NeuroScience (United States)

Studies using acute or subchronic pharmacological inhibition of phosphodiesterase 2 A (PDE2A) have led to its proposal as a target for treatment of cognitive deficits associated with neuropsychiatric and neurodegenerative disease. However, the impact of continuous inhibition of PDE2A on memory is unknown. Moreover, the neuroanatomical regions mediating memory enhancement have not been categorically identified. To address these open questions, we studied knockout mice and hippocampus restricted manipulations. Pde2a heterozygous knockout mice are viable with no gross histological abnormalities. The mice exhibit enhanced spatial and object recognition memory that is independent of anxiolytic effects and is paralleled by increased density of dendritic mushroom and thin spines in hippocampal CA3 and dentate gyrus in adult mice. In CA1, subtle alterations in spine density were seen, while theta-burst LTP and paired-pulse facilitation were normal. Spatial memory enhancement persists in aged Pde2a heterozygous knockout mice, and to our surprise these mice live significantly longer than wild-type littermate controls. In summary, we provide evidence that life-long reduction of PDE2A expression promotes spine formation and maturation, exerts beneficial effects on memory, and increases lifespan.

In order to take up new challenges regarding the management of a wide range of parameters impacting the risk of accidents at rail crossings on the Belgian railway network, we have developed an innovative multicriteria decision making framework based upon the pairwise comparison PROMETHEE (Preference Ranking METHod for Enrichment and Evaluation). The framework allows the evaluation of a global risk index based upon a wide range of indicators thanks to a “two-steps” aggregation process including the definition of sensitivity parameters. Around 50 indicators are classified into three main clusters related to three specific risk sources, namely: the road network, the rail network and the town planning related aspects. These three clusters are then aggregated into the final risk index. Within the frame of the Belgian rail network, this index provides the responsible public body with an actual strategic investment handbook regarding the most risky locations. An user friendly excel tool has been developed in order to make that new decision framework easily understandable by the final users.

Augmentation of cyclic nucleotide signaling through inhibition of phosphodiesterase (PDE) activity has long been understood to enhance memory. Efforts in this domain have focused predominantly on PDE4, a cAMP-specific phosphodiesterase implicated in consolidation. But less is known about the function of other PDEs expressed in neuroanatomical regions critical to memory. The PDE1 isoforms are the only PDEs to regulate neuronal cAMP and cGMP levels in a Ca2+/Calmodulin (CaM) dependent manner. Here, we show that knock-down of PDE1B in hippocampus of adult mice enhances contextual and spatial memory without effect on non-cognitive behaviors. Pharmacological augmentation of memory in rats was observed with a selective inhibitor of PDE1 dosed before and immediately after training, but not with drug dosed either 1 h after training or before recall. Our data clearly demonstrate a role for the PDE1B isoforms as negative regulators of memory, and they implicate PDE1 in an early phase of consolidation, but not retrieval. Inhibition of PDE1B is a promising therapeutic mechanism for treating memory impairment.

Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 μM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.

ADVERTISEMENT RETURN TO ISSUEPREVPatent HighlightNEXTPyridinonaphthyridinone Inhibitors of Type 2 Methionine AminopeptidaseGerard Rosse*View Author Information Structure Guided Chemistry, Dart Neuroscience LLC, 12278 Scripps Summit Drive, San Diego, California 92131, United States Adjunct Associate Professor, Department of Pharmacology and Physiology, College of Medicine, Drexel University, New College Building, 245 North 15th Street, Philadelphia, Pennsylvania 19102, United States*E-mail: [email protected]Cite this: ACS Med. Chem. Lett. 2015, 6, 6, 622–623Publication Date (Web):May 8, 2015Publication History Received28 April 2015Published online8 May 2015Published inissue 11 June 2015https://pubs.acs.org/doi/10.1021/acsmedchemlett.5b00177https://doi.org/10.1021/acsmedchemlett.5b00177editorialACS PublicationsCopyright © 2015 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views896Altmetric-Citations1LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (252 KB) Get e-AlertscloseSUBJECTS:Cancer,Inhibitors,Monomers,Peptides and proteins,Theoretical and computational chemistry Get e-Alerts