Novel therapeutic approaches for traumatic brain injury induced cognitive deficits

治疗创伤性脑损伤引起的认知缺陷的新方法

• 批准号: 10307126
• 负责人: SUSAN A FARR
• 金额: $ 33.14万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307126
• 关键词: Adenosine; Adenosine A3 Receptor; Adenosine Kinase; Adult; Affect; Agonist; American; Anxiety; Astrocytes; Attention; Attenuated; Biological Assay; Blood - brain barrier anatomy; Brain; Clinical Trials; Cognitive deficits; Data; Development; Dose; Drops; Enzymes; Event; FDA approved; Female; Genetic study; Head; Hippocampus (Brain); Impaired cognition; Inflammasome; Inflammatory; Injury; Interdisciplinary Study; Interleukin-1 beta; Knockout Mice; Lead; Learning; Link; Measures; Mediator of activation protein; Medical; Memory; Mental Depression; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Motor Activity; Mus; Neuraxis; Neurocognitive; Neuroglia; Neurons; Oral; Patients; Performance; Pharmacology; Pharmacology Study; Prefrontal Cortex; Preventive; Process; Public Health; Purine Nucleosides; Purinergic P1 Receptors; Reaction Time; Receptor Signaling; Regulation; Reporting; Role; Safety; Signal Transduction; Specificity; Stress; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Time; Traumatic Brain Injury; Validation; Weight; antagonist; cognitive development; cognitive function; cognitive process; cognitive task; cost; curative treatments; extracellular; genetic approach; insight; interdisciplinary approach; male; marenostrin; metabolomics; mild traumatic brain injury; mitochondrial dysfunction; mouse model; neuroinflammation; neuronal circuitry; novel; novel therapeutic intervention; preservation; prevent; preventive intervention; receptor; response; targeted treatment

Deficits in participation-level performance of specific cognitive tasks are one of the primary cognitive impairments reported after a mild TBI.3 There are no FDA-approved preventive or curative interventions. Mitochondrial dysfunction4-10 and neuroinflammation11-15 in the central nervous system (CNS) are postulated as underlying causes of cognitive impairment. Our preliminary data suggests that dysregulation of adenosine metabolism and loss of signaling at the A3 adenosine receptor (AR) subtype (A3AR) is key to these processes. Extracellular adenosine is regulated by ectonucleotidases and adenosine kinase and preliminary results in a mouse model of mild-TBI (close head weight drop)2,16 revealed that TBI altered the expression of these enzymes in the prefrontal cortex (PFC) and hippocampus. This was associated with time dependent development of memory and learning deficits [Novel Object/Place Recognition (NOPRT) and T-maze tests]. Supplementing adenosine signaling with highly selective, orally bioavailable, CNS penetrant A3AR agonists given therapeutically significantly attenuated TBI-induced memory and learning deficits 4 weeks after injury without any confounding influence on locomotor activity. Moreover, pilot data now links A3AR agonism to the inhibition of TBI-induced oxidative/nitrative stress (nitroxidative stress), neuroinflammation and activation of nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. Our findings are very exciting since A3AR agonists (e.g., IB-MECA) are already in advanced clinical trials for other indications with a good safety profile.17,18 Two Specific Aims will test our hypothesis: dysregulation of adenosinergic signaling in the brain contributes to TBI-induced cognitive impairment; restoring adenosinergic signaling with highly selective A3AR agonists is an effective strategy for therapeutic intervention. A multidisciplinary approach is used in male and female mice. Pharmacological and genetic studies as well as time course and dose responses with selective A3AR agonists are proposed. Studies will also include A3AR antagonists and A3AR knockout mice to confirm selectivity of response. In Aim 1, we will examine whether a decrease in adenosine signaling at the A3AR contributes to TBI-induced cognitive deficits. In Aim 2, we will 1) examine whether restoring A3AR signaling with A3AR agonists ameliorates TBI-induced cognitive deficits, 2) validate A3AR as a target for therapeutic intervention with selective A3AR agonists and 3) investigate their mechanism of action by examining their impact on the mitochondrial dysfunction and neuroinflammatory processes that are intimately linked to the development of cognitive deficits. Our multidisciplinary research plan is anticipated to provide evidence for the applicability of highly selective A3AR agonists to preserve cognitive function following TBI while investigating their underlying protective mechanism(s).

特定认知任务的参与级表现不足是主要认知之一 在轻度TBI后报告的障碍。3没有FDA批准的预防或治愈性干预措施。 线粒体功能障碍4-10和神经炎症11-15在中枢神经系统（CNS）中假定为 认知障碍的根本原因。我们的初步数据表明腺苷失调 A3腺苷受体（AR）亚型（A3AR）处的代谢和信号传导丢失是这些过程的关键。 细胞外腺苷受到核苷酸酶和腺苷激酶的调节，初步结果是 轻度-TBI的小鼠模型（关闭头部重量下降）2,16显示TBI改变了这些表达 前额叶皮层（PFC）和海马中的酶。这与时间相关 记忆和学习缺陷的发展[新颖对象/位置识别（NOPRT）和T迷宫测试]。 用高度选择性，口服生物利用的CNS渗透A3AR激动剂补充腺苷信号传导 鉴于治疗明显减弱了TBI诱导的记忆和学习缺陷4周后 没有对运动活动的任何混淆影响。此外，飞行员数据现在将A3AR激动剂链接到 抑制TBI诱导的氧化/硝酸应激（氮氧化应激），神经炎症和激活 含有含含吡啶的受体pyrin域3（NLRP3）炎症体。自A3AR以来，我们的发现非常令人兴奋 激动剂（例如IB-MECA）已经在高级临床试验中，以确保其他指示 配置文件17,18两个具体目标将检验我们的假设：大脑中腺苷能信号的失调 导致TBI引起的认知障碍；用高选择性A3AR恢复腺苷能信号传导 激动剂是治疗干预的有效策略。男性和 雌鼠。药理学和遗传研究以及时间过程和剂量反应有选择性 提出了A3AR激动剂。研究还将包括A3AR拮抗剂和A3AR敲除小鼠以确认 响应的选择性。在AIM 1中，我们将检查A3AR处的腺苷信号传导的减少 导致TBI引起的认知缺陷。在AIM 2中，我们将1）检查是否还原A3AR信号传导 用A3AR激动剂改善TBI诱导的认知缺陷，2）验证A3AR作为治疗的目标 选择性A3AR激动剂的干预和3）研究其作用机理，通过检查其作用机理 对线粒体功能障碍和神经炎症过程的影响，与 认知缺陷的发展。预计我们的多学科研究计划将为 在研究时，高度选择性A3AR激动剂在TBI后保留认知功能 他们的潜在保护机制。