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Therapeutic Relevance of Cannabinoids for Alzheimer's Disease

大麻素对阿尔茨海默病的治疗意义

基本信息

批准号：
9977821
负责人：
Pamela Anne Maher
金额：
$ 52.91万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
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：
2020-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977821
关键词：
Address Affect Affinity Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Animals Area Binding Bioinformatics Biological Biological Assay Brain Brain Pathology CNR1 gene CNR2 gene Cannabinoids Cannabis Carbon Dioxide Cell physiology Chemicals Chemistry Clinic Cognition Collaborations Complex Data Dementia Disease Drug Screening Drug Targeting Endocannabinoids Flavones Funding Gene Expression Goals Health Hemp Hippocampus (Brain)Human Investigational Drugs Laboratories Lead Ligands Medicinal Plants Medicine Metabolism Mississippi Modeling Molecular Molecular Target Mus Natural Products Nerve Degeneration Neurodegenerative Disorders Neurons Pathologic Pathology Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase I Clinical Trials Phenotype Plant Extracts Plants Plasma Political Factor Positioning Attribute Precipitation Property Proteins Proteomics Running Safety Secure Structure Structure-Activity Relationship System Technology Terpenes Testing Therapeutic Therapeutic Uses Time Toxic effect Transgenic Mice Transgenic Organisms Treatment Efficacy United States National Institutes of Health Universities Work base clinical development drug candidate drug discovery endogenous cannabinoid system familial Alzheimer disease high reward high risk in vivo interest mouse model neuron loss neuroprotection new therapeutic target novel phase I trial prevent receptor safety testing screening small molecule small molecule libraries social factors tau phosphorylation tissue culture transcriptome sequencing

项目摘要

Alzheimer's disease (AD) is the most prevalent old age-associated neurodegenerative disease. However, despite extensive interest and financial outlay, drug discovery in this area has not yet yielded any disease modifying compounds. This may be in part due to the small number of molecular targets suitable for drug discovery. Thus, the identification of multiple, new drug targets is still one of the most important challenges. Natural products are the structural basis of the majority of the drugs in the clinic today. Over the last decade we have used a novel phenotypic drug-screening platform based upon toxicities associated with the old brain and natural product chemical libraries and plant extracts to identify compounds that have therapeutic efficacy in multiple models of neurodegeneration and dementia. Structure-activity relationship driven medicinal chemistry was then used to make pharmacologically suitable drug candidates. One of these compounds is in Phase I clinical trials for AD and another has NIH funding for investigational new drug (IND) studies. Perhaps the greatest relatively unexplored area of AD drug discovery is the endocannabinoid system and the compounds in the Cannabis plant that may interact with it and other pathways associated with neurodegeneration. While THC and CBD are the best-studied chemicals in Cannabis, there are over 100 non-psychoactive cannabinoids and 400 other unique chemicals within the plant that may have therapeutic potential. We have recently demonstrated that several of these compounds are exceptionally neuroprotective in our drug screening platform that has already yielded bona fide AD drug candidates. The hypothesis for this high risk, high reward R21 application is that there are non-psychoactive compounds within the Cannabis plant that are suitable lead drug candidates for AD, and that these can be identified, along with their molecular targets, by our drug screening platform and chemical proteomics, respectively. There are three Specific Aims in this application. 1) All commercially available pure cannabinoids, flavones and terpenes in Cannabis, will be screened, a project already underway. In collaboration with Dr. ElSohly at the University of Mississippi, additional pure compounds will be screened that he has isolated as well as complex high CBD Cannabis (hemp) extracts where the most active new compounds will be identified. The pharmacological and safety properties of the five best compounds will be studied. 2) The molecular targets of one will be determined. 3) Finally, the therapeutic efficacy of the best compound will be examined in the 3xFAD transgenic mouse model of familial AD and rapidly aging SAMP8 mice. At the end of two years, a non-psychoactive compound and its target will have been identified and tested in two rigorous models of dementia, gaining a greater understanding of the therapeutic potential of Cannabis as well as identifying a novel lead AD drug candidate and its molecular target.

阿尔茨海默病（AD）是最常见的老年相关神经退行性疾病。然而,