DART NeuroScience LLC

San Diego, CA, United States

DART NeuroScience LLC

San Diego, CA, United States
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Bhattacharyya S.,King's College London | Crippa J.A.,University of Sao Paulo | Allen P.,King's College London | Martin-Santos R.,King's College London | And 13 more authors.
Archives of General Psychiatry | Year: 2012

Context: The aberrant processing of salience is thought to be a fundamental factor underlying psychosis. Cannabis can induce acute psychotic symptoms, and its chronic use may increase the risk of schizophrenia. We investigated whether its psychotic effects are mediated through an influence on attentional salience processing. Objective: To examine the effects of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) on regional brain function during salience processing. Design: Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of Δ9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli. Setting: University center. Participants: Fifteen healthy men with minimal previous cannabis use. Main Outcome Measures: Symptom ratings, task performance, and regional brain activation. Results: During the processing of oddball stimuli, relative to placebo, Δ9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. Δ9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of Δ9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of Δ9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation. Conclusions: Δ9- Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders. ©2012 American Medical Association. All rights reserved.


Goren M.A.,New York Medical College | Morizumi T.,University of Toronto | Menon I.,New York Medical College | Joseph J.S.,Scripps Research Institute | And 6 more authors.
Nature Communications | Year: 2014

Opsin, the rhodopsin apoprotein, was recently shown to be an ATP-independent flippase (or scramblase) that equilibrates phospholipids across photoreceptor disc membranes in mammalian retina, a process required for disc homoeostasis. Here we show that scrambling is a constitutive activity of rhodopsin, distinct from its light-sensing function. Upon reconstitution into vesicles, discrete conformational states of the protein (rhodopsin, a metarhodopsin II-mimic, and two forms of opsin) facilitated rapid (>10,000 phospholipids per protein per second) scrambling of phospholipid probes. Our results indicate that the large conformational changes involved in converting rhodopsin to metarhodopsin II are not required for scrambling, and that the lipid translocation pathway either lies near the protein surface or involves membrane packing defects in the vicinity of the protein. In addition, we demonstrate that β2 -adrenergic and adenosine A 2A receptors scramble lipids, suggesting that rhodopsin-like G protein-coupled receptors may play an unexpected moonlighting role in re-modelling cell membranes.


Peters M.,Dart Neuroscience LLC | Bletsch M.,Dart Neuroscience LLC | Stanley J.,Dart Neuroscience LLC | Wheeler D.,Dart Neuroscience LLC | And 2 more authors.
Neuropsychopharmacology | Year: 2014

Aging is associated with declines in memory and cognitive function. Here, we evaluate the effects of HT-0712 on memory formation and on cAMP response element-binding protein (CREB)-regulated genes in aged mice. HT-0712 enhanced long-term memory formation in normal young mice at brain concentrations similar to those found to increase CRE-mediated gene expression in hippocampal neurons. Aged mice showed significantly poorer contextual and trace conditioning compared with young-adult mice. In aged mice, a single injection of HT-0712 significantly boosted contextual and trace long-term memory. Additional effects of HT-0712 were seen in a spatial memory task. Our parallel biochemical experiments revealed that inductions of the CREB-regulated genes, cFos, Zif268, and Bdnf, after fear conditioning were diminished in aged mice. HT-0712 facilitated expression of these CREB-regulated genes in aged hippocampus, indicating that the drug engages a CREB-regulated mechanism in vivo. These findings corroborate and extend our previous results on the mechanism of action of HT-0712 and its efficacy to enhance memory formation. Our data also indicate that HT-0712 may be effective to treat age-associated memory impairment in humans.Neuropsychopharmacology advance online publication, 30 July 2014; doi:10.1038/npp.2014.154.


Xia B.,Dart Neuroscience LLC | de Belle S.,Dart Neuroscience LLC | de Belle S.,Canyon Crest Academy
Aging | Year: 2016

Accumulating evidence suggests that early-life diet may program one's health status by causing permanent alternations in specific organs, tissues, or metabolic or homeostatic pathways, and such programming effects may propagate across generations through heritable epigenetic modifications. However, it remains uninvestigated whether postnatal dietary changes may program longevity across generations. To address this question of important biological and public health implications, newly-born flies (F0) were collected and subjected to various post-eclosion dietary manipulations (PDMs) with different protein-carbohydrate (i.e., LP, IP or HP for low-, intermediate- or high-protein) contents or a control diet (CD). Longevity and fecundity analyses were performed with these treated F0 flies and their F1, F2 and F3 offspring, while maintained on CD at all times. The LP and HP PDMs shortened longevity, while the IP PDM extended longevity significantly up to the F3 generation. Furthermore, the LP reduced while the IP PDM increased lifetime fecundity across the F0-F2 generations. Our observations establish the first animal model for studying transgenerational inheritance of nutritional programming of longevity, making it possible to investigate the underlying epigenetic mechanisms and identify gene targets for drug discovery in future studies. © Xia and de Belle.


Gomez L.,Dart Neuroscience LLC | Breitenbucher J.G.,Dart Neuroscience LLC
Bioorganic and Medicinal Chemistry Letters | Year: 2013

Phosphodiesterase inhibition has received much attention in the past 20 years for the potential treatment of CNS disorders. A primary focus of this work is the enhancement of memory and/or cognitive functioning. The role of PDEs in the augmentation of cyclic nucleotide signaling makes these enzymes attractive targets for enhancing the effects of neuronal communication. This review focuses on recent findings with respect to the role of PDE2 inhibition in cognitive functioning. Special attention is paid to recently disclosed, selective tool compounds and the use of these tool compounds to support the role of PDE2 inhibition in cognition. Recently reported SAR and modeling work will be presented along with discussion of the entry of new PDE2 inhibitors into the clinic. © 2013 Elsevier Ltd. All rights reserved.


Patent
Dart Neuroscience Llc | Date: 2014-03-11

The invention provides a chemical entity of Formula (I) wherein R^(1), R^(2), R^(3), R^(4), Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting PDE4, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating peripheral disorders, including inflammatory and renal disorders.


Patent
Dart Neuroscience Llc | Date: 2014-03-11

The invention provides a chemical entity of Formula (I) wherein R^(1), R^(2), R^(3), Y, and n have any of the values described herein and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting MAO, and MAO-B selectively, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating treating peripheral disorders (including obesity, diabetes, and cardiometabolic disorders) and their associated co-morbidities.


Patent
Dart NeuroScience LLC | Date: 2014-03-14

Systems and methods for treating patients to improve cognitive or motor abilities are disclosed. One exemplary method comprises receiving a visiting patient at a clinic, administering an augmenting agent to the visiting patient, training the visiting patient to stimulate neuronal activity, and recording augmenting agent administration data and patient training data associated with the visiting patient. The augmenting agent may comprise a phosphodiesterase 4 (PDE 4) inhibitor. The method may further comprise receiving a returning patient at the clinic, administering the augmenting agent to the returning patient, training the returning patient to stimulate neuronal activity, and recording augmenting agent administration data and patient training data associated with the returning patient.


Patent
Dart Neuroscience Llc | Date: 2014-03-11

The invention provides a chemical entity of Formula (I) wherein R^(1), R^(2), R^(3), R^(4), Y and Z have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting PDE4, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating peripheral disorders, including inflammatory and renal disorders.


Patent
Dart Neuroscience Llc | Date: 2014-03-11

The invention provides a chemical entity of Formula (I) wherein R^(1), R^(2), R^(3), Y, and n have any of the values described herein and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting MAO, and MAO-B selectively, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating peripheral disorders (including obesity, diabetes, and cardiometabolic disorders) and their associated co-morbidities.

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