Terry A.V.,Georgia Regents University |
Callahan P.M.,Georgia Regents University |
Bertrand D.,HiQScreen Sarl
Journal of Pharmacology and Experimental Therapeutics | Year: 2015
The nicotine metabolite cotinine (1-methyl-5-[3-pyridynl]-2-pyrrolidinone), like its precursor, has been found to exhibit procognitive and neuroprotective effects in some model systems; however, the mechanism of these effects is unknown. In this study, both the R-(+) and S-(-) isomers of cotinine were initially evaluated in an extensive profiling screen and found to be relatively inactive across a wide range of potential pharmacologic targets. Electrophysiological studies on human α4β2 and α7 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes confirmed the absence of agonistic activity of cotinine at α4β2 or α7 nAChRs. However, a significant increase in the current evoked by a low concentration of acetylcholine was observed at α7 nAChRs exposed to 1.0 mMR-(+)-or S-(-)-cotinine. Based on these results, we used a spontaneous novel object recognition (NOR) procedure for rodents to test the hypothesis that R-(+)-or S-(-)-cotinine might improve recognition memory when administered alone or in combination with the Alzheimer's disease (AD) therapeutic agent donepezil. Although both isomers enhanced NOR performance when they were coadministered with donepezil, neither isomer was active alone. Moreover, the procognitive effects of the drug combinations were blocked by methyllycaconitine and dihydro-β-erythroidine, indicating that both α7 and α4β2 nAChRs contribute to the response. These results indicate that cotinine may sensitize α7 nAChRs to low levels of acetylcholine (a previously uncharacterized mechanism), and that cotinine could be used as an adjunctive agent to improve the effective dose range of cholinergic compounds (e.g., donepezil) in the treatment of AD and other memory disorders. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
Hurst R.,Pfizer |
Rollema H.,Rollema Biomedical Consulting |
Bertrand D.,HiQScreen Sarl
Pharmacology and Therapeutics | Year: 2013
Substantial progress in the identification of genes encoding for a large number of proteins responsible for various aspects of neurotransmitter release, postsynaptic detection and downstream signaling, has advanced our understanding of the mechanisms by which neurons communicate and interact. Nicotinic acetylcholine receptors represent a large and well-characterized family of ligand-gated ion channels that is expressed broadly throughout the central and peripheral nervous system, and in non-neuronal cells. With 16 mammalian genes identified that encode for nicotinic receptors and the ability of the subunits to form heteromeric or homomeric receptors, the repertoire of conceivable receptor subtype combinations is enormous and offers unique possibilities for the design and development of new therapeutics that target nicotinic acetylcholine receptors. The aim of this review is to provide the reader with recent insights in nicotinic acetylcholine receptors from genes, structure and function to diseases, and with the latest findings on the pharmacology of these receptors. Although so far only a few nicotinic drugs have been marketed or are in late stage development, much progress has been made in the design of novel chemical entities that are being explored for the treatment of various diseases, including addiction, depression, ADHD, cognitive deficits in schizophrenia and Alzheimer's disease, pain and inflammation. A pharmacological analysis of these compounds, including those that were discontinued, can improve our understanding of the pharmacodynamic and pharmacokinetic requirements for nicotinic 'drug-like' molecules and will reveal if hypotheses on therapies based on targeting specific nicotinic receptor subtypes have been adequately tested in the clinic. © 2012 Elsevier Inc.
Agency: Cordis | Branch: FP7 | Program: CP | Phase: ICT-2007.3.6 | Award Amount: 5.16M | Year: 2008
NEMSIC addresses the future intelligent sensor and actuator systems in which solid-state semiconductor micro/nanodevices and micro/nano-mechanical devices are co-integrated for new functionalities and increased performance.The project proposes the exploration and development of low power sensing micro/nanosystems based on Nano-Electro-Mechanical (NEM) structures integrated on a Silicon-On-Insulator (SOI) or Silicon-On-Nothing (SON) technological platform. The applications that drive the technological NEM-based smart system demonstrators are gas (COx, NOx, SOx) and biological sensing (DNA, proteins and other molecules), dedicated to critical environment monitoring and applications in the fields of genetics, pharmacology and drug discovery. NEM technology will be combined with silicon CMOS technology involving novelty and scientific/technical challenges at three levels: (i) system level, addressing the challenge of true nano-micro interfaces, where signals detected by arrays of nanostructures are processed by smartly designed low power CMOS circuitry, (ii) device level, where novel true hybrid NEM-FET devices support new highly sensitive detection scheme and power management via sleep switches and (iii) technology level, where nanotechnology processes (top down processed nanobeams and nanogaps, featuring sub-100nm dimensions) will be developed and combined with advanced functionalization techniques for dedicated sensing that stays compatible with CMOS in future IC-embedded or post-IC approaches. The reliability of the NEM structures, combined with prospects for 0-level packaging are studied as key challenges for the success of such Nano-electro-mechanical-system-integrated-circuits (NEMSIC).Finally, NEMSIC is expected to provide the end-users with flexible design methodologies based on advanced but well-controlled SOI or SON technology platforms, with predictable performances and associated cost effectiveness.
Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.1.1-5 | Award Amount: 14.64M | Year: 2008
Cys-loop receptors (CLRs) form a superfamily of structurally related neurotransmitter-gated ion channels, comprising nicotinic acetylcholine, glycine, GABA-A/C and serotonin (5HT3) receptors, crucial to function of the peripheral and central nervous system. CLRs cover a wide spectrum of functions, ranging from muscle contraction to cognitive functions. CLR (mal)function is linked to various disorders, including muscular dystrophies, neurodegenerative diseases, e.g. Alzheimers and Parkinsons, and neuropsychiatric diseases, e.g. schizophrenia, epilepsy and addiction. CLRs are potentially important drug targets for treatment of disease. However, novel drug discovery strategies call for in depth understanding of ligand binding sites, the structure-function relationships of these receptors and insight into their actions in the nervous system. NeuroCypres assembles the expertise of leading European laboratories to provide a technology workflow, which enables to embark on this next step in CLR structure and function. A major target of this project is to obtain high-resolution X-ray and NMR structures for CLRs and their complexes with diverse ligands, agonists/antagonists, channel blockers and modulators, which will reveal basic mechanisms of receptor functioning from ligand binding to gating and open new avenues to rational drug design. In addition, the project aims at understanding receptor function in the context of the brain, focusing on receptor biosensors, receptor-protein interactions and transgenic models. This major challenge requires application and development of a multidisciplinary workflow of high-throughput (HT) crystallization and HT-electrophysiology technologies, X-ray analysis, NMR and computational modeling, fragment-based drug design, innovative quantitative methods of interaction-proteomics, sensitive methods for visualization of activity and localization of receptors and studies of in vitro and in vivo function in animal models of disease.
Agency: Cordis | Branch: FP7 | Program: CSA | Phase: ICT-2011.9.5 | Award Amount: 1.71M | Year: 2011
Guardian Angels (GA) are future zero-power, intelligent, autonomous systems-of-systems featuring sensing, computation, and communication beyond human aptitudes. GA will assist humans from their infancy to old age in complex life situations and environments. Zero-power reflects system-of-systems ability to scavenge energy in dynamic environments by disruptive harvesting techniques. The project prepares zero-power technologies based on future energy-efficient technologies, heterogeneous design, and disruptive energy scavengers.\nThree zero-power generations of GAs are foreseen: Physical Guardian Angels are zero-power, on-body networks or implantable devices that monitor vital health signals and take appropriate actions to preserve human health. Environmental Guardian Angels extend monitoring to dynamic environments, using disruptive scavengers, personalized data communication, and first thinking algorithms. They are personal assistants that protect their wearers from environment dangers. Emotional Guardian Angels are intelligent personal companions with disruptive zero-power, manmachine interfaces deployed at large scale. They sense and communicate using non-verbal languages playing an important role in health, education, and security worldwide. This project addresses the following scientific challenges for energy-efficient visionary Guardian Angel autonomous systems: (i) energy-efficient computing (down to E=10-100kT), (ii) and communication (approaching the limit of 1pJ/bit), (iii) low-power sensing, (iv) disruptive scavenging (bio-inspired, thermoelectric, etc, targeting energy densities of tens of mW/cm2), and (v) zero-power man-machine interfaces. A selection of emerging technologies based on energy efficiency is proposed. We will also develop design tools that integrate electrical, mechanical, optical, thermal, and chemical simulation tools over length and time scales currently not achievable.