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) 会导致严重的医疗、经济和 社会负担。 TBI 导致 TBI 患者和动物模型的酒精摄入量增加。一项挑战是 TBI 和共病 AUD（TBI 后酗酒）很难用目前的治疗方案来控制。 另一个挑战是缺乏 TBI 后酗酒的分子机制。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 报道称，N-乙酰血清素（NAS）通过针对多种神经毒性和炎症提供保护。 组织损伤。然而，目前尚不清楚 NAS 是否可以减轻 TBI 后的 AUD。这个假设的中心假设 转化项目是 NAS 减轻 TBI 引起的饮酒。总体目标是开发一个 新型 NAS 疗法可减轻 TBI 增加的酒精摄入量和偏好，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 (TrkB)/Akt 的机制 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 是一种有效的 TrkB 激动剂，BDNF/TrkB 通路在饮酒中发挥重要作用。 2）我们和其他人 报道称 NAS 抑制培养神经元的神经毒性，并为脑损伤动物模型提供保护 缺血和视网膜缺血再灌注。 3）我们和其他人报道NAS可以保护肝细胞凋亡 和肝缺血再灌注损伤，并通过 TrkB 激活作用于昼夜节律。 4）我们的初步数据 表明 NAS 可以减轻 TBI 引起的酒精摄入和偏好、认知能力下降和神经行为 一些小鼠体内的缺陷，并防止划痕和乙醇处理的培养神经元细胞的神经毒性， TBI 后酒精使用的体外细胞损伤模型。 5) 我们发现 NAS 可以减少白介素-1β（IL-1 和 IL- 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，以及 6) 我们发现 NAS 可以缓解 TBI 诱导的饮酒暴露小鼠的 BDNF 减少。 目标 1 将测试 NAS 是否能减轻 TBI 引起的饮酒、神经退行性变和认知能力 和小鼠神经行为损伤，并确定 TrkB 缺乏是否至少部分降低 NAS TrkB 敲除小鼠的益处。目标2将确定NAS的保护机制是否被介导 通过调节 BDNF 表达、激活 TrkB/Akt 通路、抑制炎症等 NAS 的 BDNF/TrkB/Akt 通路的调节是通过使用 TrkB 敲除小鼠激活 TrkB 来介导的。 这项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 后滥用。主要优势包括： i) 使用 TBI、AUD 以及 TBI 引起的酒精摄入量和 偏好动物模型； ii) 对NAS在多种组织损伤中的研究具有丰富的经验；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 澳元、饮酒、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.