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REDWOOD CITY, CA, United States

Xiong X.,Stanford University | Barreto G.E.,Stanford University | Xu L.,Stanford University | Ouyang Y.B.,Stanford University | And 3 more authors.

Background and Purpose- Stroke causes brain injury with activation of an inflammatory response that can contribute to injury. We tested the hypothesis that the anti-inflammatory cytokine interleukin-4 (IL-4) reduces injury after stroke using IL-4 knockout (KO) adult male mice. Methods- IL-4 KO and wild-type mice were subjected to transient middle cerebral artery occlusion. Outcome was assessed by triphenyltetrazolium chloride staining for infarct volume, neuroscore and spontaneous activity for behavioral outcome, and immunostaining and stereological counting for cellular response. Results- Infarction volume at 24 hours was significantly larger in IL-4 KO mice, neurological score was significantly worse, and spontaneous activity was reduced compared with wild-type mice. Increased macrophage/microglial infiltration, increased numbers of myeloperoxidase-positive cells, and increased Th1/Th2 ratio were observed in the infarct core in IL-4 KO mice. Reduced astrocyte activation was observed in the cortical penumbra in IL-4 KO mice. Recombinant IL-4 administered intracerebroventricularly before middle cerebral artery occlusion significantly reduced infarct volume, improved neurological score, reduced macrophages/microglia, and lowered the Th1/Th2 ratio in IL-4 KO mice, but not in wild-type. Conclusions- Loss of IL-4 signaling in KO mice was associated with worse outcome, and this was reversed by giving exogenous IL-4. Worsened outcome was associated with increased inflammation in the core, which was reversed in IL-4 KO but not significantly changed in wild-type mice by exogenous IL-4. This is consistent with IL-4 signaling leading to reduced inflammation in the core and a possible beneficial role for activated astrocytes in the penumbra. Copyright © 2011 American Heart Association. All rights reserved. Source

Afasci, Inc., Kansas State University and The Regents Of The University Of California | Date: 2014-09-30

Tricyclic pyrone compounds having high oral bioavailability, excellent blood-brain barrier permeability, and low toxicity are presented. Administration of the compounds to Alzheimers Disease transgenic models resulted in substantially reduced soluble and insoluble A species in the brain without affecting general behavior and motor coordination. Furthermore, in addition to blocking the toxicity and formation of both intraneuronal and extracellular A aggregates, the compounds also increase cellular cholesterol efflux, restore axonal trafficking, and enhance hippocampal synaptic plasticity.

Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 852.60K | Year: 2013

DESCRIPTION (provided by applicant): Sleep deprivation (SD) occurs universally in modern societies and causes significant social and financial harm. Numerous human and animal studies indicate that various forms of SD are deleterious to mental and physicalhealth. Therefore, SD has been recognized as an unmet challenge to public health. There is increased need to study the effects of different forms of SD on physiological functions in animal models. However, better methods are sorely needed. Existing SD systems have low throughput and capacity and are difficult to use and expensive. In our Phase I project, we have developed an automatic sleep monitoring/sleep deprivation system for rodents. Our system is based on floor sensors, the data from which yield automatic sleep scoring. We demonstrated that hands-off automatic SD using our method is technically feasible. We have also verified the advantages of our system over other competing systems, namely, that our method is less invasive, more selective, less time-consuming, and easier to use. Based on the success of our Phase I project, our Phase II project will be focused on the commercialization of our research product. The objective of the present project is to develop a unified, non-invasive, high throughput and low cost SD system for mice and rats. Our specific aims are the follows. Aim 1. Development of a full-featured SD system with multiple lines of hardware and software products Aim 1a. Development of Hardware. We will refine, ruggedize, and make more reliable our mouse SD system while simultaneously lowering the costs for mass production. Because rats are used frequently in sleep research we will develop a rat SD system based on the mouse SD system. Aim 1b. Development of software. We will develop softwareproducts with the following innovative features: 1) Establish bi-directional information exchange through USB cable to perform three common types of SD: acute SD, sleep fragmentation and chronic sleep restriction; 2) Create a user-friendly interface for flexible experimental design on the host PC; 3) Expand system capability to perform simultaneous studies in as many as 64 rats or mice. 4) Extend the software functionality to perform group statistical analysis including group means, standard errors and data lists in animals from multiple groups of animals, and 5) Extend the software products to both 32-bit and 64-bit Windows XP, Vista and Windows 7 platforms. Aim 2. Evaluation and validation of the SD system, and development of standardized SD protocols The validation of the system includes: 1) verification of sleep loss and rebound following SD using EEG evaluation and verification of the robustness and ease of use of the system, 2) investigation of the consequences of SD on animals, especially social recognition/preference tasks, and 3) development of an experimental cook book through performing different types of SD to standardize SD protocols in order to facilitate comparison results generated by different laboratories. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The aim of the present project is to develop an automated, noninvasive, high throughput and low lost sleep deprivation system for rodents. This system can help to study sleep loss impact on health and drug discovery for the treatment of sleep disorders.

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 233.24K | Year: 2015

DESCRIPTION provided by applicant Preclinical evaluation of treatment strategies for retinal neurodegenerative diseases is highly dependent on mouse models Classical methods to assess the visual function of animals such as electroretinogram ERG which measures electrical responses in the retina do not address connections between the eye and brain or visual perception by the visual system This often raises concerns regarding the functional relevance of the therapeutic benefit Difficulty in assessing visual perception and related behavior in mice and rats largely due to their subtle visual behavior cues and the lack of adequate measuring devices presents a critical barrier to the application of mouse models for evaluating treatment efficacy of new drugs and for scaling up for behavior phenotyping to screen genetic vision defects Pupillary light reflex PLR and optokinetic reflex OKR tests are useful methods in clinics for assessing human visual responses and perception However such tests have been difficult to conduct in rodents because current rodent visual testing methods or devices either do not allow accurate quantitative assessment for PLR or OKR or use subjective measures to score visual responses To address these challenges we propose to advance the technology by designing an easy to use automated platform that employs an eye pupil tracking device equipped with a computer vision system chiefly the interactive tracking system for unambiguous objective scoring of visual responses Our proposed new device will allow real time quantitative and accurate assessment of rodent visual function including light responses visual acuity and contrast sensitivity The novelty of our system also lies in that it does not require complicated calibration procedures needed in commonly used human eye tracking Rather than precisely measuring the extent of eye turning or orientation we propose to detect the signature eye movement in accordance with the speed and direction of visual stimuli The system will be validated using normal wildtype mice and mouse models of retinal neurodegeneration known to develop visual behavior changes in the parameters mentioned above Although rodent eye tracking has been investigated before this proposed visual assessment system would be the first commercially viable product that uses an eye pupil tracking device to automatically assess visual perception in rodents The combined PLR and OKR tests and vastly simplified and automated quantification methods will also provide the first scalable behavior platform for phenotyping and drug discovery in the vision research area In the future this technology has the potential of being expanded to measure responses from various visual stimuli This may translate into broader applications for evaluating brain diseases that afflict the visual pathways This platform for mouse visual behavior assessment will therefore greatly facilitate drug discovery and development aimed at preventing and slowing vision loss or restoring sight helping to combat devastating blinding conditions such as age related macular degeneration AMD and glaucoma PUBLIC HEALTH RELEVANCE The objective of the current proposal is to design and develop an automated system for the measure of rodent mice and rats light response visual acuity and contrast sensitivity The system will apply human eye pupil tracking techniques for objective and unambiguous evaluation of light response and visual perception This platform will provide a powerful tool for phenotypic studies as well as for discovery of new drugs that can prevent or restore sight caused by blinding conditions such as age related macular degeneration and glaucoma

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 596.06K | Year: 2013

DESCRIPTION (provided by applicant): Development of Novel Tricyclic Pyrone Drugs for Treatment of Alzheimer's Disease Alzheimer's disease (AD) afflicts approximately 35 million people worldwide and is the most common cause of dementia in the elderly. Thereis an unmet medical need for new AD therapeutic development. Amyloid-b (Ab) deposited in AD brains has been hypothesized to initiate a cascade of molecular changes leading to synaptic dysfunction, inflammation, and neuronal death observed in AD brains. Therefore, designing therapies targeting Ab and downstream events have become a major effort in AD drug development. We have taken the rational design approach and synthesized a class of tricyclic pyrone compounds (TPs). The lead compounds CP2 and TP70 werefound to have high oral bioavailability, excellent blood-brain barrier permeability, and low toxicity. Administering compounds either orally or intraperitoneally to young AD transgenic models in 'preventive studies' resulted in substantially reduced soluble and insoluble Ab species in the brain and preserved memory and motor function. Furthermore, we have found that in addition to being able to block the toxicity and formation of both intraneuronal and extracellular A aggregates, the lead TPs also increasecellular cholesterol efflux, restore axonal trafficking, and enhance hippocampal synaptic placidity - these synergistic cellular actions could be potential mechanisms underlying in vivo effects. The discovery of these lead TP compounds comes from the collaboration among Dr. Hua, a medicinal chemist, Dr. Jin, an AD neuropathology expert, and recently the PI Dr. Xie, who has substantial experience in pharmaceuticals and contributed to drug development in the CNS therapeutic area. Dr. Xie at AfaSci started with developing the SmartCageTM system and then has taken advantage of the technology in translational research. In the proposed project with the support of this phase I SBIR, we will thoroughly study pharmacokinetics (PK) and in vivo pharmacodynamics (PD)of the lead TPs, through accomplishment of the following Specific Aims: 1. Focus on two novel lead compounds CP2 and TP70 in the therapeutic studies: We will generate PK/PD and ADME (absorption, distribution, metabolism, and excretion) profiles of lead compounds. We will focus on investigating the in vivo efficacy (neurobehavioral and neuropathological outcomes) of lead compounds by oral administration to the AD model APP/PS1 mice. These studies will provide evidence-based selection of a therapeutic candidate using the criteria of druggable PK profile, in vivo efficacy especially in cognition, and improved pathologic outcomes. 2. Utilization of novel lead compounds LRL22 and LRL50 as backup compounds, if needed, and preparation for good manufacturing practice (GMP) production of the selected therapeutic candidate. Although we have identified five top backup TP compounds, we will use our previously discovered novel leads LRL22 and LRL50 which possess different chemical structures from TP, but alsoshown inhibition of Ab-induced toxicity and neuroprotection as backup compounds. The backup compounds will be re-synthesized and ready to be tested in vivo as described in Aim 1, should both CP2 and TP70 not fulfill the criteria of therapeutic candidates. We will also optimize the chemical synthesis process in preparation for GMP production of the identified therapeutic candidate for a Phase II study. Success in the Phase I study will prepare for investigational new drug (IND)-enabling studies in a PhaseII project. Our ultimate goal is to translate our preclinical discovery of the novel TP compounds into clinical therapeutic candidates that possess AD disease-modifying properties. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is the major cause of dementia and one of the most disabling health conditions worldwide. Current drugs only have modest effects and there is an unmet need to develop more effective and safer medicines for the treatment of AD. We here propose tostudy two novel tricyclic pyrone compounds that show potent cell protective action against Ab toxicity for their potential to treat cognitive impairment and slow disease progression in an animalmodel of AD.

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