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Mechanism based evaluation of botanical bioactive compounds enhancing neurological resilience (Project 2)

基于机制的植物生物活性化合物增强神经恢复能力的评估（项目2）

基本信息

批准号：
10231796
负责人：
Doris Kretzschmar
金额：
$ 19.53万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10231796
关键词：
Acids Address Affect Age Aging Antioxidants Arylalkylamine N-Acetyltransferase Ashwagandha Attention Ayurvedic Medicine Biological Assay Blood Vessels Botanical dietary supplements Botanicals Brain Chemicals Choline O-Acetyltransferase Clinical Trials Cognition Cognitive Coupled Courtship Crude Extracts Dose Drosophila genus Drosophila inturned protein Drosophila melanogaster Elderly Electron Transport Evaluation Fingerprint Future GABA Receptor Gene Expression Glycosides Goals Gotu kola Head Health Herb Hippocampus (Brain)Human Immunohistochemistry In Vitro Individual Invertebrates Lactones Liquid Chromatography Locomotion Mammals Mass Spectrum Analysis Materials Testing Measures Mediating Mental Depression Mitochondria Modeling Molecular Moods Mus Neurologic Neurons Neurotransmitters Oxidative Stress Parents Pathway interactions Plant Roots Population Proteins Reactive Oxygen Species Resolution Response Elements Rodent Model Role Serotonin Signal Transduction Sleep Slice Statistical Methods Steroids Symptoms Synapses Testing Triterpenes Water age related age related neurodegeneration base design experimental study fly gamma-Aminobutyric Acid improved in vivo in vivo Model inhibitor/antagonist insight madecassic acid mating behavior mouse model neurotropic relating to nervous system resilience response sleep pattern sleep regulation vasoconstriction vibration

项目摘要

PROJECT SUMMARY_PROJECT 2 The design of valid clinical trials involving botanical dietary supplements requires the optimization of the trial product such that it contains sufficient levels of the active compounds. The identification of these active compounds therefore has to be a part of any serious study of botanicals. It is also recognized that the overall activity profile of a botanical may be mediated by multiple active compounds, which can act independently, additively, synergistically or be antagonistic to each other. While functional effects of a botanical can be demonstrated in vivo, initial studies on the identification of active compounds and their interaction is most efficiently evaluated using in vitro, ex vivo, or moderate throughput in vivo approaches. These also have the advantage of being mechanism based. Centella asiatica (CA) and Withania somnifera (WS) have been shown to affect cognition, sleep and mood and in this project, we will use primary neuron assays, brain slices, and Drosophila models to explore mechanisms and active compounds of CA and WS. Primary neurons will be used to address effects of CA and WS and their compounds on neuronal health by measuring neuronal arborization, antioxidant responses, reactive oxygen species, and mitochondrial function. In addition, we will determine effects on vascular tone and resilience to vasoconstriction in mouse brain slices to test whether these extracts promote vascular health. Drosophila models will be used to identify compounds that improve the age-related decline in locomotion and reactivity. We will also test effects on a described depression-like state in Drosophila, using courtship as an assay, and we will measure Serotonin levels in neuronal subpopulations identified as mediating this depression-like state. Furthermore, Drosophila will be used to determine effects on sleep patterns, which are also altered by age in flies and mammals. The cellular and molecular pathways regulating sleep are well known in Drosophila and we can therefore also investigate whether CA and/or WS promotes healthy sleep patterns by altering neuronal activity and neurotransmitter signaling in the neuronal populations that promote or suppress sleep. Besides Serotonin and Aceteylcholine, this includes GABA. To expand these studies to the mouse model, we will measure neuronal activity in mouse brain slices and address whether treatment with CA and/or WS affects GABA signaling (using GABA inhibitors). Together, these studies will identify active compounds in CA and WS and they will show whether they support health and resilience by promoting cognition, sleep and/or mood. In addition, they will provide insights into mechanism that may mediate these effects, like improving neuronal activity, decreasing oxidative stress and/or promoting mitochondrial function. Future studies can then confirm these effects in an in vivo mouse model and eventually provide the basis for testing active compounds in humans.

项目摘要项目2