Cannabinoid Modulation of Recovery from HIV-Associated Synaptic Toxicity

大麻素对 HIV 相关突触毒性恢复的调节

• 批准号: 7385609
• 负责人: Stanley A Thayer
• 金额: $ 18.69万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-13 至 2009-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385609
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Agonist; Anti-Retroviral Agents; Antiemetics; Appetite Stimulants; Back; Biological Assay; CNR1 gene; Cannabinoids; Cell Death; Central Nervous System Infections; Cessation of life; Chromosome Pairing; Condition; DLG4 gene; Detection; Development; Disease; Endocannabinoids; Excision; Excitatory Neurotoxins; Exposure to; Foundations; Future; Glutamates; HIV; HIV tat Protein; HIV-1; Hippocampus (Brain); Hour; Image; Impaired cognition; In Vitro; Lasers; Maintenance; Microglia; Morphology; Neurocognitive; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Neurotoxins; Numbers; Patients; Pharmaceutical Preparations; Proteins; Rattus; Receptor Activation; Recovery; Role; Scaffolding Protein; Scanning; Synapses; Synaptic Transmission; Testing; Tetrahydrocannabinol; Time; Toxic effect; Toxin; Virus Shedding; base; brain cell; cannabinoid receptor; density; drug of abuse; enhanced green fluorescent protein; excitotoxicity; improved; macrophage; multicatalytic endopeptidase complex; neuron loss; neurotoxic; neurotoxicity; neurotransmission; postsynaptic; receptor; research study; tat Protein

DESCRIPTION (provided by applicant): Changes in dendritic morphology such as dendritic pruning precede neuronal cell death in many neurodegenerative disorders, including HIV-1 associated dementia (HAD). The loss of synaptic connections associated with dendritic degeneration correlates with cognitive decline in these disorders. Antiretroviral treatment initially improves neurocognitive function in HAD patients. Preliminary studies quantified intact postsynaptic densities (PSDs) in rat hippocampal neurons grown in primary culture by imaging clusters of the scaffolding protein PSD95 fused to enhanced green fluorescent protein (PSD95-EGFP). This unique imaging based assay enables the number of synaptic connections between the same hippocampal neurons to be recorded over time. HIV-1 proteins and excitotoxins caused significant loss of PSD95-EGFP puncta at concentrations that failed to produce overt neuronal death. PSD loss preceded cell death and was reversible. Synaptic activity is required for the development and stability of synapses and cannabinoids, drugs given to AIDS patients clinically and widely used illicitly, modulate excitatory neurotransmission and excitotoxicity. The hypothesis that cannabinoid agonists slow recovery of synapses following exposure to excitotoxins or HIV proteins will be tested. A detailed time course for recovery of PSD95-EGFP puncta following removal of toxin will be recorded and the effects of pharmacological block of excitatory synaptic transmission determined. A cannabinoid receptor full agonist, the partial agonist ?9-tetrahydrocannabinol and a receptor antagonist will be used to evaluate the role of varying degrees of CB1 receptor activation and endocannabinoid tone on recovery of PSDs. Cannabinoid receptor agonists are predicted to impair the ability of neurons to integrate back into the synaptic network following neurotoxic insult. If cannabinoids inhibit synaptic recovery, these studies would caution against recreational use of cannabinoids or their use as antiemetics and appetite stimulants in patients with HAD. This project may provide a foundation for future studies to evaluate the effects of drugs of abuse on the recovery of neural function following HIV-1 infection of the central nervous system.

描述（由申请人提供）：在许多神经退行性疾病（包括 HIV-1 相关痴呆（HAD））中，树突形态的变化（例如树突修剪）先于神经元细胞死亡。与树突变性相关的突触连接丧失与这些疾病的认知能力下降相关。抗逆转录病毒治疗最初可以改善 HAD 患者的神经认知功能。初步研究通过对与增强型绿色荧光蛋白 (PSD95-EGFP) 融合的支架蛋白 PSD95 簇进行成像，量化了原代培养中生长的大鼠海马神经元的完整突触后密度 (PSD)。这种独特的基于成像的测定能够随着时间的推移记录相同海马神经元之间的突触连接数量。 HIV-1 蛋白和兴奋毒素在未能产生明显神经元死亡的浓度下导致 PSD95-EGFP 斑点显着损失。 PSD 损失先于细胞死亡并且是可逆的。突触活动是突触和大麻素的发育和稳定性所必需的，大麻素是临床上给予艾滋病患者并广泛非法使用的药物，可调节兴奋性神经传递和兴奋性毒性。大麻素激动剂在暴露于兴奋毒素或 HIV 蛋白后会减缓突触恢复的假设将得到检验。将记录去除毒素后 PSD95-EGFP 点恢复的详细时间过程，并确定兴奋性突触传递的药理学阻断的效果。大麻素受体完全激动剂、部分激动剂α9-四氢大麻酚和受体拮抗剂将用于评估不同程度的CB1受体激活和内源性大麻素张力对PSD恢复的作用。大麻素受体激动剂预计会损害神经元在神经毒性损伤后整合回突触网络的能力。如果大麻素抑制突触恢复，这些研究将警告 HAD 患者不要娱乐性使用大麻素或将其用作止吐剂和食欲兴奋剂。该项目可为未来研究评估滥用药物对中枢神经系统 HIV-1 感染后神经功能恢复的影响奠定基础。