Novel therapeutic approaches for traumatic brain injury induced cognitive deficits

在特定认知任务的参与水平表现上的缺陷是主要认知之一 轻度脑损伤后报告的损害3没有FDA批准的预防性或治疗性干预措施。 中枢神经系统(CNS)的线粒体功能障碍4-10和神经炎症11-15被认为是 认知障碍的根本原因。我们的初步数据表明，腺苷的调节失调 A3腺苷受体(AR)亚型(A3AR)的代谢和信号丢失是这些过程的关键。 胞外腺苷受胞外核糖核酸酶和腺苷激酶的调节，初步结果显示 轻度头部减重的小鼠模型2，16显示颅脑损伤改变了这些基因的表达 前额叶皮质(PFC)和海马体中的酶。这与时间依赖有关 记忆和学习障碍的发展[新奇物体/位置识别(NOPRT)和T迷宫测试]。 用高选择性、口服生物利用度高的中枢神经系统A3AR激动剂补充腺苷信号 在创伤后4周给予治疗性显著减轻脑损伤所致记忆和学习障碍 对运动活动没有任何混杂的影响。此外，飞行员数据现在将A3AR激动症与 抑制脑损伤诱导的氧化/硝化应激(亚硝化应激)、神经炎症和激活 含NLRP3的结节样受体3(NLRP3)炎症体。自从A3AR以来，我们的发现非常令人兴奋 激动剂(如IB-MECA)已经处于其他适应症的高级临床试验中，安全性很好 17，18两个特定的目标将检验我们的假设：大脑中腺苷能信号的失调 有助于脑外伤引起的认知障碍；通过高选择性的A3AR恢复腺苷能信号 激动剂是一种有效的治疗干预策略。在Male和Male使用了多学科方法 雌性老鼠。药理学和遗传学研究以及选择性药物的时间和剂量反应 A3AR激动剂被提出。研究还将包括A3AR拮抗剂和A3AR基因敲除小鼠以证实 响应的选择性。在目标1中，我们将检查A3AR上腺苷信号的减少 会导致脑外伤引起的认知障碍。在目标2中，我们将1)检查是否恢复A3AR信号 使用A3AR激动剂改善颅脑损伤引起的认知障碍，2)验证A3AR作为治疗靶点 选择性A3AR激动剂的干预和3)通过检测其作用机制 对线粒体功能障碍和神经炎症过程的影响，这些过程与 认知缺陷的发展。我们的多学科研究计划有望为 高选择性A3AR激动剂在脑外伤后认知功能保护中的适用性研究 他们潜在的保护机制(S)。

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).