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Endocannabinoid-mediated neuroprotection in models of neuroAIDS in vivo

体内神经艾滋病模型中内源性大麻素介导的神经保护

基本信息

批准号：
9906196
负责人：
Sylvia Fitting
金额：
$ 36.26万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906196
关键词：
2-arachidonylglycerol AM 251 AM630 Affect Alzheimer&apos s Disease Animal Model Animals Anti-Inflammatory Agents Antiinflammatory Effect Astrocytes Behavior Behavioral Behavioral inhibition Benzodiazepine Receptor Brain Brain Diseases CNR1 gene CNR2 gene Cannabis Chronic Chronic Disease Cognitive Cognitive deficits Consequences of HIV Decision Making Defect Disease Electrophysiology (science)Endocannabinoids Enzyme Inhibition Enzyme Inhibitor Drugs Enzymes Exhibits FAAH inhibitor Goals HIV HIV Envelope Protein gp120 HIV-1 HIV-associated neurocognitive disorder High Prevalence Imaging Techniques Impulsivity In Vitro Individual Infection Inflammation Inflammatory Injury Investigation Knowledge Laboratories Ligands Location Longitudinal Studies MAGL inhibitor Magnetic Resonance Imaging Medial Mediating Modeling Monitor Monoacylglycerol Lipases Morphology Nerve Degeneration Nervous System Trauma Neurocognitive Deficit Neurodegenerative Disorders Neuroglia Neuromodulator Neuronal Injury Operant Conditioning Parkinson Disease Pathology Patients Peripheral Pharmacology Physiological Play Positron-Emission Tomography Prefrontal Cortex Process Property Proteins Role Site Specificity Structure Synapses Testing Therapeutic Therapeutic Uses Toxic effect Tracer Training Transgenic Mice Vertebral column anandamide antiretroviral therapy cognitive function density endocannabinoid signaling endogenous cannabinoid system excitotoxicity executive function fatty acid amide hydrolase hippocampal pyramidal neuron imaging study in vivo in vivo imaging inflammatory marker inhibitor/antagonist interest longitudinal positron emission tomography memory consolidation mouse model nervous system disorder neuroAIDS neurocognitive disorder neuroinflammation neuron development neuronal survival neuroprotection new therapeutic target non-invasive imaging pre-clinical preclinical study prevent protective effect receptor response rimonabant side effect synaptic function synthetic cannabinoid tat Protein therapeutic target tool treatment response

项目摘要

Project Summary/Abstract Several neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases, display alterations in the function of the endocannabinoid (eCB) system. In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is now considered a chronic disease with an inflammatory component that specifically targets the brain and causes a high prevalence of HIV-associated neurocognitive disorders (HAND). The eCB system has attracted interest as a target for treatment of neurodegenerative disorders, due to the potential neuroprotective, anti-inflammatory, & neurotrophic properties of CBs. However, therapeutic use of eCBs in vivo is unlikely due to their rapid degradation by catabolic enzymes. The main enzymes responsible for degradation of two major eCBs, anandamide (AEA) and 2-arochinonoylglycerol (2- AG), are respectively: fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MAGL). A new class of selective inhibitors of those enzymes has been developed that show neuroprotective and anti-inflammatory effects in preclinical animal models of neurodegenerative diseases. These new pharmacological tools allow for selective elevation of eCB signaling, which enables investigation of physiological actions of particular eCBs as well as reveal therapeutic potential of such precise modulation. The aim of the present study is to unravel the role of the eCB signaling in neuroprotection against HIV-1 protein toxicity that results in behavioral changes as a consequence of HAND. To achieve this goal, we plan to use Tat and gp120 transgenic (tg) mice, as well- established models of neuroAIDS, that will allow us to determine: 1) the neuroprotective effects of eCBs on prefrontal cortex (PFC)-dependent behavior in vivo, with use of catabolic enzyme inhibition; 2) the mechanisms underlying protective effects of eCBs in PFC ex vivo; and 3) the effects of chronic eCB catabolic enzyme inhibitors on neuroinflammation using positron emission tomography (PET) imaging in vivo. We hypothesize that in the HIV-1 protein tg mouse models, eCB catabolic enzyme inhibitors will show protective effects on behavior, function, and structure via a CB1R/CB2R-mediated mechanism. In Specific Aim 1, Tat tg mice will be trained on the operant conditioning Go/No-Go task and eCB enzyme inhibitors will be tested for protective effects against Tat-induced interference in cognitive function, including a decrease of behavioral inhibition and increased impulsivity. Moreover, the same animals will undergo electrophysiology studies on PFC pyramidal neurons ex vivo to establish the effects of eCB enzyme inhibitors on synaptic currents. In Specific Aim 2, we will conduct behavioral, functional, and morphological imaging studies to determine if eCBs are neuroprotective in Tat toxicity via a CB1R/CB2R-mediated mechanism ex vivo. In Specific Aim 3, non-invasive longitudinal PET imaging studies in Tat and gp120 tg mice will investigate the effects of eCB enzyme inhibitors on active inflammatory processes using the tracer [18F]-PBR111. Understanding the role of the eCB system in neuro- AIDS may uncover novel therapeutic targets for HAND and other diseases in which cognitive deficits occur.

项目总结/文摘