N-acetylserotonin alleviates neurotoxicity in alcohol misuse following TBI

N-乙酰血清素可减轻 TBI 后酒精滥用造成的神经毒性

• 批准号: 10591834
• 负责人: Xin Wang
• 金额: $ 23.01万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10591834
• 关键词: Address; Adult; Affinity; Agonist; Alcohol consumption; Alcohol-Induced Disorders; Alcohol-Induced Neurotoxicity; Alcohols; American; Animal Model; Animals; Anti-Inflammatory Agents; Antidepressive Agents; Antioxidants; Apoptosis; Apoptotic; Astrocytes; Biological Assay; Brain; Brain-Derived Neurotrophic Factor; Cell model; Cells; Cerebellum; Cerebral Ischemia; Circadian Rhythms; Clinical; Cognitive; Cognitive deficits; Corpus striatum structure; Cultured Cells; Data; Diagnosis; Economics; Enzyme-Linked Immunosorbent Assay; Ethanol; Functional disorder; Glial Fibrillary Acidic Protein; Goals; Hepatocyte; Hippocampus; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Inflammation; Injury; Interleukin-1 beta; Interleukin-6; Intervention; Knockout Mice; Mediating; Medical; Modeling; Molecular; Mus; Nerve Degeneration; Neurons; Neuroprotective Agents; Outcome; Pathogenesis; Pathway interactions; Performance; Pharmaceutical Preparations; Play; Post-Traumatic Stress Disorders; Publications; Receptor Protein-Tyrosine Kinases; Recording of previous events; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Research; Risk Factors; Role; Serum; Silver Staining; Solid; TBI Patients; TBI treatment; Testing; Traumatic Brain Injury; Veterans; Western Blotting; alcohol comorbidity; alcohol misuse; alcohol use disorder; cell injury; disability; drug development; drug discovery; experience; fluoro jade; in vivo; liver ischemia; multidisciplinary; neurobehavioral; neurotoxicity; novel; novel therapeutics; preference; prevent; protective effect; receptor; retinal ischemia; social; success; tissue injury

Traumatic brain injury (TBI) and comorbid alcohol use disorder (AUD) cause heavy medical, economic, and social burdens. TBI drives the escalation of alcohol intake in TBI patients and animal models. One challenge is that TBI and comorbid AUD (alcohol misuse following TBI) is difficult to manage with current treatment options. Another challenge is that the molecular mechanisms underlying alcohol misuse following TBI are lacking. Thus, it is urgently needed to explore novel therapies and molecular mechanisms for AUD following TBI. We and others reported that N-acetyl-serotonin (NAS) offers protection by targeting neurotoxicity and inflammation in various tissue injuries. However, it is unknown whether NAS alleviates AUD following TBI. The central hypothesis of this translational project is that NAS mitigates TBI-induced alcohol consumption. The overall goal is to develop a novel NAS therapy to alleviate TBI-increased alcohol intake and preference and elucidate its protective mechanisms by regulating brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrkB)/Akt pathway, and inflammation. This study is supported by preliminary data and prior research: 1) NAS is a potent agonist of TrkB, and the BDNF/TrkB pathway plays an important role in alcohol consumption. 2) we and others report that NAS inhibits neurotoxicity in cultured neurons and offers protection in animal models of cerebral ischemia and retinal ischemia-reperfusion. 3) we and others reported that NAS protects hepatic cell apoptosis and hepatic ischemia-reperfusion injury and acts on circadian rhythm by TrkB activation. 4) our preliminary data suggest that NAS alleviates TBI-induced alcohol intake and preference, cognitive decline, and neurobehavioral deficit in a few mice in vivo and prevents neurotoxicity in scratch- and ethanol-treated cultured neuronal cells, a cell injury model of alcohol use following TBI in vitro. 5) we show that NAS reduces interleukin-1β (IL-1 and IL- 6 releases in scratch- and ethanol-treated astrocytes, another cell injury model of alcohol use following TBI, and 6) we found that NAS alleviates BDNF reduction in TBI-induced alcohol consumption exposed mice. Aim 1 will test whether NAS alleviates TBI-induced alcohol consumption, neurodegeneration, and cognitive and neurobehavioral impairments in mice and determine whether TrkB deficiency, at least partly, reduces NAS’s benefits in TrkB knockout mice. Aim 2 will determine whether the protective mechanisms of NAS are mediated by regulating BDNF expression, activating TrkB/Akt pathway, and inhibiting inflammation as well as the regulation of BDNF/TrkB/Akt pathway of NAS are mediated by activation of TrkB using TrkB knockout mice. The success of this study will make an important contribution to drug discovery and pathogenesis for alcohol misuse following TBI. Key strengths include: i) Usage of TBI, AUD, and TBI-induced alcohol intake and preference animal models; ii) Extensive experience in the study of NAS in a variety of tissue injuries; and iii) A strong team with interdisciplinary and complementary expertise and an excellent history of collaborative publications in the fields of AUD, alcohol consumption, inflammation, neurotoxicity, and drug development.

创伤性脑损伤（TBI）和合并症酒精疾病（AUD）导致大量医疗，经济和 社会伯恩斯。 TBI推动了TBI患者和动物模型中酒精摄入量的升级。一个挑战是 TBI和合并症AUD（TBI之后的酒精滥用）很难通过当前的治疗选择来管理。 另一个挑战是缺乏TBI后酒精滥用的分子机制。那， 迫切需要探索新的疗法和分子机制，以实现TBI之后的AUD。我们和其他人 报道N-乙酰基 - 羟基素（NAS）通过靶向各种神经毒性和炎症提供了保护 组织损伤。但是，尚不清楚NAS是否减轻TBI之后的AUD。中心假设 转化项目是NAS减轻TBI诱导的饮酒量。总体目标是开发 新颖的NAS疗法可减轻TBI吸收的酒精摄入量并偏爱并阐明其保护性 通过控制脑衍生的神经营养因子（BDNF），酪氨酸受体激酶B（TRKB）/AKT的机制 途径和炎症。这项研究得到了初步数据和先验研究的支持：1）NAS是一种有效的 TRKB的激动剂和BDNF/TRKB途径在饮酒中起着重要作用。 2）我们和其他人 报告NAS抑制培养神经元中的神经毒性，并在脑模型中提供保护 缺血和视网膜缺血再灌注。 3）我们和其他人报告说NAS保护肝细胞凋亡 和肝缺血 - 再灌注损伤，并通过TRKB激活对昼夜节律作用。 4）我们的初步数据 建议NAS减轻TBI引起的酒精摄入和偏好，认知能力下降和神经行为 几只小鼠体内缺陷，并防止刮擦和乙醇处理的培养神经元细胞中的神经毒性，A TBI在体外使用酒精的细胞损伤模型。 5）我们表明NAS减少了白介素1β（IL-1和IL- 6个在刮擦和乙醇处理的星形胶质细胞中释放，TBI后的另一个细胞损伤模型，以及 6）我们发现NAS减轻了TBI诱导的饮酒暴露小鼠的BDNF降低。 AIM 1将测试NAS是否减轻TBI诱导的酒精消耗，神经退行性和认知 小鼠的神经行为障碍，并确定TRKB缺乏症至少部分减少了NAS TRKB淘汰小鼠的好处。 AIM 2将确定NAS的受保护机制是否介导 通过调节BDNF表达，激活TRKB/AKT途径并抑制注射以及 使用TRKB基因敲除小鼠激活TRKB，介导了NAS的BDNF/TRKB/AKT途径的调节。 这项研究的成功将为酒精的药物发现和发病机理做出重要贡献 TBI滥用。关键优势包括：i）使用TBI，AUD和TBI诱导的酒精摄入量以及 偏好动物模型； ii）在各种组织损伤中进行NAS研究的丰富经验；和iii）a 拥有跨学科和完整专业知识的强大团队以及合作的良好历史 AUD，酒精消费，注射，神经毒性和药物开发领域的出版物。