N-acetylserotonin alleviates neurotoxicity in alcohol misuse following TBI

创伤性脑损伤(TBI)和共病酒精使用障碍(AUD)造成严重的医疗、经济和 社会负担。脑外伤导致脑外伤患者和动物模型酒精摄入量的增加。其中一个挑战是 用目前的治疗方案很难控制脑损伤和并发的AUD(脑损伤后的酒精滥用)。 另一个挑战是缺乏脑外伤后酒精滥用的分子机制。因此， 因此迫切需要探索新的治疗方法和分子机制来治疗颅脑损伤后的AUD。我们和其他人 据报道，N-乙酰-5-羟色胺(NAS)通过靶向神经毒性和炎症在不同的 组织损伤。然而，目前尚不清楚NAS是否能缓解脑损伤后的AUD。这一点的中心假设是 翻译项目是NAS减轻了脑损伤引起的酒精消耗。总体目标是开发一种 新的NAS疗法减轻脑外伤后酒精摄入量和嗜酒性增加及其保护作用 脑源性神经营养因子、酪氨酸受体蛋白B/Akt的调控机制 途径，和炎症。这项研究得到了初步数据和先前研究的支持：1)NAS是一种强有力的 TrkB激动剂和BDNF/TrkB通路在饮酒中起着重要作用。2)我们和其他人 NAS抑制培养神经元的神经毒性并在脑损伤动物模型中提供保护的研究报告 缺血和视网膜缺血再灌流。3)我们和其他人报道了NAS保护肝细胞凋亡 肝缺血再灌注损伤，并通过激活TrkB作用于昼夜节律。4)我们的初步数据 提示NAS可减轻脑外伤所致的酒精摄取和嗜好、认知能力下降和神经行为 在少数小鼠体内缺失，并防止划痕和乙醇处理培养的神经细胞的神经毒性，a 酒精致体外脑损伤后细胞损伤模型的建立。5)我们发现非刺激性刺激物可降低白介素1β(IL-1和IL-1 DNA)。 6在划痕和乙醇处理的星形胶质细胞中的释放，这是继脑损伤后酒精使用的另一种细胞损伤模型，以及 6)我们发现NAS可减轻脑损伤后饮酒小鼠脑源性神经营养因子的减少。 Aim 1将测试NAS是否能缓解脑损伤引起的酒精消耗、神经退行性变和认知 和小鼠的神经行为损伤，并确定TrkB缺乏是否至少部分减少了NAS 对TrkB基因敲除小鼠的好处。目标2将确定NAS的保护机制是否通过 通过调节BDNF的表达，激活TrkB/Akt通路，抑制炎症反应，以及 通过TrkB基因敲除小鼠激活TrkB，调节NAS的BDNF/TrkB/Akt通路。 这项研究的成功将对酒精的药物发现和发病机制做出重要贡献 脑外伤后误用。主要优点包括：i)使用TBI、AUD和TBI诱导的酒精摄入，以及 首选动物模型；ii)在各种组织损伤中研究NAS的丰富经验；以及iii)A 具有跨学科和互补专业知识的强大团队，以及出色的协作历史 AUD、酒精消费、炎症、神经毒性和药物开发领域的出版物。

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.