AZD0328 To Treat Traumatic Brain Injury

AZD0328 治疗创伤性脑损伤

• 批准号: 10343886
• 负责人: Charles S Cox
• 金额: $ 35.09万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-17 至 2023-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10343886
• 关键词: Acetylcholine; Acute; Agonist; American; Antiinflammatory Effect; Attention; Blood - brain barrier anatomy; Brain; Brain Injuries; Brain Pathology; Cause of Death; Cells; Cerebral Edema; Chemicals; Clinical Research; Clinical Trials; Cognitive; Common Data Element; Communication; Data; Data Analyses; Dextrans; Diffusion Magnetic Resonance Imaging; Dose; Drug Kinetics; Elements; Extravasation; Female; Functional disorder; Funding; Hippocampus (Brain); Image; Immune; Immune system; Impaired cognition; Inflammation; Inflammatory; Informatics; Informed Consent; Injections; Injury; Interleukin-1 beta; Interleukin-6; Intervention; Intervention Studies; Ipsilateral; Label; Lead; Learning; Life; Logistics; Measures; Memory; Methods; Modeling; Neurotransmitters; Neutrophil Infiltration; Neutrophilic Infiltrate; Outcome; Outcome Measure; Parietal Lobe; Pathologic Processes; Pathway interactions; Patients; Performance; Peripheral; Pharmacologic Substance; Phase; Positron-Emission Tomography; Process; Protocols documentation; Public Health; Rattus; Receptor Activation; Regimen; Research; Rodent; Rodent Model; Role; Safety; Secondary to; Sex Differences; Signal Pathway; Spleen; Splenocyte; System; TNF gene; Testing; Therapeutic; Time; Tissues; Traumatic Brain Injury; United States; Vagus nerve structure; Vulnerable Populations; alpha-bungarotoxin receptor; axon injury; base; blood-brain barrier permeabilization; clinically relevant; cognitive function; cognitive testing; cytokine; data management; data sharing; disability; efficacy study; experience; experimental study; genotyped patients; improved; improved outcome; indexing; injured; injury-related death; macrophage; male; member; memory recognition; neuroinflammation; neuronal survival; nonhuman primate; novel; object recognition; patient population; preclinical study; primary outcome; programs; radioligand; regenerative; response; screening; survival outcome; systemic inflammatory response; treatment response; uptake; vagus nerve stimulation; water maze

Project Summary/Abstract Traumatic brain injury (TBI) is a leading cause of death and disability with approximately 1.7 million incidents occurring each year. There is an urgent need to develop new treatments that would limit brain pathology and improve overall outcome. Recently, a signaling pathway has been described that by which the brain regulates systemic inflammation. Specifically, this pathway acts on α7 nicotinic acetylcholine receptors (α7nAChR) present on peripheral immune cells to decrease inflammation. Activation of these receptors using chemical agonists decreases TBI-triggered inflammation, reduces blood-brain barrier permeability and improves cognitive outcome. The α7nAChR agonist AZD0328, developed by AstraZeneca, has been shown to improve cognitive function in normal rodents and non-human primates. However, it has not been tested if AZD0328 can reduce TBI-triggered inflammation, reduce brain pathology, or improve outcome. We propose to test the overall hypothesis that AZD0328 will reduce inflammation in rats following TBI (primary outcome). Further, it is anticipated that AZD0328 will reduce BBB permeability, brain pathology and improve cognitive outcome. If beneficial effects are observed, we will proceed to the planning of a Phase II efficacy study. We propose two aims to test our hypothesis: Aim 1 (UG3): To examine if AZD0328 reduces peripheral and central inflammation and improves outcome in traumatically brain injured rats. Aim 2 (UH3): Clinical Trial Planning.

项目摘要/摘要 创伤性脑损伤(TBI)是导致死亡和残疾的主要原因，约有170万起 每年都会发生。迫切需要开发新的治疗方法，以限制大脑病理和 改善总体结果。最近，一条信号通路被描述出来，大脑通过它来调节 全身炎症。具体地说，该途径作用于α7烟碱型乙酰胆碱受体(α7nAChR) 存在于外周免疫细胞上，以减少炎症。使用化学物质激活这些受体 激动剂减少脑损伤引发的炎症，降低血脑屏障通透性，改善认知能力 结果。阿斯利康公司开发的α7nAChR激动剂AZD0328已被证明可以改善认知能力 在正常啮齿动物和非人灵长类动物中的功能。然而，AZD0328是否可以减少，还没有经过测试 脑外伤引发的炎症，减轻大脑病理，或改善预后。我们建议测试一下整体 假设AZD0328将减轻大鼠脑损伤后的炎症(主要结果)。更进一步说，它是 预期AZD0328可降低血脑屏障通透性，改善脑病理，改善认知结局。如果 观察到有益的效果后，我们将着手规划第二阶段疗效研究。我们建议两个 旨在验证我们的假设：目标1(UG3)：检查AZD0328是否可以减少外周和中枢炎症 并改善脑创伤大鼠的预后。目标2(UH3)：临床试验计划。