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Investigation of endocannabinoid-mediated neuroprotection in models of neuroAIDS

神经艾滋病模型中内源性大麻素介导的神经保护作用的研究

基本信息

批准号：
9135623
负责人：
Sylvia Fitting
金额：
$ 22.25万
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：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9135623
关键词：
2-arachidonylglycerol AM630 Acquired Immunodeficiency Syndrome Address Alzheimer&apos s Disease Anti-Anxiety Agents Anti-Inflammatory Agents Anti-inflammatory Brain Brain Diseases CB1 knockout CB1 receptor antagonist CB2 knockout CB2 receptor antagonist CNR1 gene CNR2 gene Cell Death Cells Chronic Disease Cognitive deficits Defect Dendrites Disease Electrophysiology (science)Endocannabinoids Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes FAAH inhibitor Functional disorder Funding Genetic Glutamates Goals Grant HIV-1 HIV-associated neurocognitive disorder High Prevalence Homeostasis In Vitro Individual Infection Injury Investigation Ions Knockout Mice Knowledge Laboratories Ligands MAGL inhibitor Mediating Modeling Monoacylglycerol Lipases Monoglycerides Morphology Multiple Sclerosis Mus Nerve Degeneration Neuraxis Neurocognitive Deficit Neurodegenerative Disorders Neuronal Dysfunction Neuronal Injury Neurons Neuroprotective Agents Parkinson Disease Pathology Pathway interactions Pharmacology Physiologic pulse Prefrontal Cortex Process Property Role SR 141716A Slice Synapses Synaptic plasticity Time Toxic effect Vertebral column anandamide antiretroviral therapy cannabinoid receptor cellular imaging density endocannabinoid signaling endogenous cannabinoid system excitotoxicity extracellular fatty acid amide hydrolase in vivo inhibitor/antagonist innovation nervous system disorder neurocognitive disorder neuroinflammation neuroprotection neurotoxicity neurotransmission new therapeutic target painful neuropathy patch clamp presynaptic prevent public health relevance receptor research study therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): The endocannabinoid system has an important role in many neurodegenerative and neuroinflammatory processes/diseases including Parkinson's disease, Alzheimer's disease, and neuropathic pain. In the era of combined antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) is now considered a chronic disease that specifically targets the brain and causes a high prevalence of mild forms of neurocognitive impairments, also referred to as HIV-associated neurocognitive disorders (HAND) [1, 2]. The best correlate of HAND has been shown to be synaptodendritic damage with injury to synapses and dendrites underlying the neurocognitive impairments seen in HIV-1 positive individuals [3]. It is proposed that increasing endocannabinoid signaling will be protective in models of such neuronal damage. Preliminary studies from our laboratory have shown that anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) used as direct ligands are neuroprotective against HIV-1 Tat-induced dysfunction and injury. However, use of endocannabinoids in vivo is not optimal/feasible because of their rapid degradation by catabolic enzymes: the main enzyme responsible for degradation of AEA, fatty acid amide hydrolase (FAAH), and the main enzyme responsible for degradation of 2-AG, monoacylglycerol lipase (MAGL). Recently, a new class of selective inhibitors of those enzymes have been developed that show neuroprotective, anti-inflammatory, antinociceptive and anxiolytic effects [4-6]. Thus, the focus of this proposal is to determine 1) the neuroprotective effects of endocannabinoids in HIV-1 Tat-induced injury using endocannabinoid catabolic enzyme inhibitors as a tool, and to define 2) the receptor- mediated mechanisms by which endocannabinoids are naturally protective in HIV-1 Tat neurotoxicity. We hypothesize that endocannabinoids will be protective in neuro-acquired immunodeficiency syndrome (neuroAIDS) via a presynaptic CB1 receptor-dependent mechanism. In Specific Aim 1, we will determine the mechanisms by which FAAH inhibitor PF3845 and MAGL inhibitor MJN110 are neuroprotective against HIV-1 Tat toxicity. Cell imaging and electrophysiology studies on cultured prefrontal cortex neurons will assess the effects of the enzyme inhibitors on HIV-1 Tat-induced disturbances of ion homeostasis (i.e. increases in [Ca2+]I and [Na+]i), synaptic neurotransmission, synaptodendritic injury and cell death. In Specific Aim 2, we will determine if endocannabinoids are naturally neuroprotective in HIV-1 Tat-induced toxicity via a presynaptic CB1 receptor-mediated pathway. Whole cell-patch clamp recordings will be conducted ex vivo on prefrontal cortex slices of CB1 and CB2 knockout mice, including paired-pulse stimulation, dual whole patch recordings, and extracellular cell-attached recordings. New knowledge will be gained about how the endocannabinoid system protects neurons from HIV-1 Tat-induced toxicity by focusing on changes in synaptic plasticity of excitation and inhibition. Understanding the effects of enzyme inhibitors in the context of neuroAIDS may uncover novel therapeutic targets for HAND and other diseases in which cognitive deficits occur.