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）导致严重的医疗，经济和社会问题。 社会负担。TBI驱动TBI患者和动物模型中酒精摄入量的增加。一个挑战是 TBI和合并的AUD（TBI后酒精滥用）很难用目前的治疗方案进行管理。 另一个挑战是缺乏TBI后酒精滥用的分子机制。因此，在本发明中， 因此迫切需要探索TBI后AUD的新疗法和分子机制。我们和其他人 N-acetyl-serotonin（NAS）通过靶向神经毒性和炎症提供保护， 组织损伤然而，目前尚不清楚NAS是否会在TBI后重新调整AUD。这个问题的核心假设是 翻译项目是NAS减轻TBI诱导的酒精消费。总体目标是制定一个 一种新的NAS疗法，以缓解TBI增加的酒精摄入和偏好，并阐明其保护作用 通过调节脑源性神经营养因子（BDNF）、酪氨酸受体激酶B（Trk B）/Akt 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是一种有效的 BDNF是TrkB的激动剂，BDNF/TrkB通路在酒精消耗中起重要作用。2)我们和其他人 报告说，NAS抑制培养的神经元的神经毒性，并提供保护，在动物模型的脑 缺血和视网膜缺血-再灌注。3)我们和其他人报道了NAS保护肝细胞凋亡 和肝脏缺血-再灌注损伤，并通过TrkB激活作用于昼夜节律。4)我们的初步数据 这表明，NAS抑制了TBI诱导的酒精摄入和偏好、认知能力下降和神经行为 在一些小鼠体内的缺陷，并防止在划痕和乙醇处理的培养神经元细胞的神经毒性， 体外TBI后酒精使用的细胞损伤模型。5)我们发现，NAS降低了白细胞介素-1 β（IL-1 β和IL-1 R）的表达， 6在划痕和乙醇处理的星形胶质细胞中释放，这是TBI后酒精使用的另一种细胞损伤模型， 6)我们发现NAS在TBI诱导的酒精消耗暴露小鼠中证实了BDNF的减少。 目标1将测试NAS是否能抑制TBI诱导的饮酒、神经退行性变和认知功能障碍。 和神经行为障碍，并确定TrkB缺乏是否至少部分地降低了NAS的 TrkB敲除小鼠的益处。目的2将确定NAS的保护机制是否介导 通过调节BDNF的表达，激活TrkB/Akt通路，抑制炎症， NAS的BDNF/TrkB/Akt途径的调节是通过使用TrkB敲除小鼠激活TrkB介导的。 该研究的成功将为酒精的药物发现和发病机制做出重要贡献 TBI后的误用。主要优势包括：i）使用TBI，AUD和TBI诱导的酒精摄入， ii）在各种组织损伤中研究NAS的广泛经验;和iii）A 强大的团队，具有跨学科和互补的专业知识，以及良好的合作历史 AUD、酒精消耗、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.