Brain Injury and Alcohol: Neuropathological Mechanisms of Impaired Recovery

脑损伤和酒精：恢复受损的神经病理学机制

• 批准号: 8904304
• 负责人: Sophie Xu Teng
• 金额: $ 3.95万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2016-05-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904304
• 关键词: Accident and Emergency department; Acute; Alcohol abuse; Alcohol consumption; Alcoholic Intoxication; Alcohols; Am 80; Animals; Anxiety; Behavior; Behavioral; Blood - brain barrier anatomy; Brain; Brain Injuries; Cell Adhesion Molecules; Cell Proliferation; Cell Survival; Cessation of life; Clinical Management; Clinical Research; Cognitive; Cognitive deficits; Complement; Critical Thinking; Data; Development; Development Plans; Doctor of Philosophy; Ensure; Environment; Event; Fellowship; Fostering; Free Radicals; Functional disorder; Funding; Future; Impaired cognition; Impairment; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Ipsilateral; Lateral; Lead; Leukocytes; Liquid substance; Literature; Measures; Mediator of activation protein; Memory impairment; Mental Depression; Mentorship; Molecular; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Nerve Degeneration; Nerve Regeneration; Neuroglia; Neurons; Neutrophil Infiltration; Outcome; Patients; Percussion; Permeability; Physiology; Play; Post-Concussion Syndrome; Prevalence; Preventive; Process; Prostaglandins; Recovery; Reporting; Research; Research Personnel; Resolution; Risk; Rodent Model; Role; Scientist; Site; Staging; Testing; Time; Tissues; Training; Training Programs; Translational Research; Traumatic Brain Injury; Traumatic Brain Injury recovery; Up-Regulation; adverse outcome; alcohol consequences; alcohol exposure; alcohol research; behavioral impairment; career; chemokine; cognitive function; cytokine; experience; mRNA Expression; mild traumatic brain injury; mortality; nerve stem cell; neurobehavioral; neurogenesis; neuroinflammation; neurological recovery; preclinical study; prevent; public health relevance; response; skills; success

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) represents a leading cause of morbidity and mortality among young individuals with ~1.7 million reported TBI cases in the U.S. annually. The number of victims under the influence of alcohol while sustaining a TBI is substantial. It is estimated that 36% to 51% of TBI incidents are associated with prior or concurrent alcohol use. Furthermore, many patients continue to use alcohol after TBI in up to 26% of cases. However, not many preclinical studies have examined the impact of post-injury alcohol exposure on TBI recovery and the underlying mechanisms. TBI produces neuroinflammation characterized by a cascade of events such as activation of glial cells, the release of pro-inflammatory cytokines and chemokines, upregulation of endothelial adhesion molecules, and the infiltration of circulating leukocytes. Our preliminary studies show a rapid increase of pro-inflammatory cytokine and chemokine expression at 6 h and enhanced neutrophil infiltration into the ipsilateral site of injury at 24 h post-TBI. In addition, a disrupion of blood brain barrier was observed at 24 and 72 h after TBI. Sustained inflammation is detrimental and contributes to the pathophysiological sequelae post-TBI. Alcohol exposure is a factor involved in exacerbated inflammation, and our preliminary data demonstrate that alcohol intoxication at the time of TBI prolonged the pro-inflammatory cytokine and chemokine mRNA expression at 24 h post-TBI. Therefore, we predict that post-injury alcohol exposure will enhance the neuroinflammatory cascade and prevent the resolution of inflammatory response to TBI. Moreover, prolonged inflammation may cause further brain damage and thus delay the neurological recovery post TBI. This is supported by our preliminary data that show impaired neurological recovery under the influence of post-injury alcohol exposure. Taken together, the literature and our preliminary data support our central hypothesis that post-injury alcohol exposure impairs cognitive and neurobehavioral recovery following TBI. We propose that sustained neuroinflammation is a central underlying mechanism contributing to increased neuronal death and impaired neuroregeneration following TBI. The proposed studies to be performed as part of the training of the applicant will use an integrative approach to test the predictions that 1) post-injury alcohol exposure delays cognitive, behavior, and physical recovery after TBI and that 2) post-injury alcohol exposure prevents resolution of neuroinflammation, accentuates neuronal death, and impairs neurogenesis following TBI. The findings from the proposed study will provide scientific evidence to take necessary interventions during clinical management, which may prevent further alcohol-induced secondary damage and the mechanisms associated with accelerated neurodegenerative changes following TBI.

描述（由申请人提供）：脑外伤（TBI）代表了美国每年约有170万例TBI病例的年轻人中发病率和死亡率的主要原因。在维持TBI的同时，在酒精影响下的受害者人数是大量的。据估计，36％至51％的TBI事件与先验或同时使用的酒精有关。此外，在多达26％的病例中，许多患者在TBI后继续使用酒精。但是，没有多少临床前研究检查了伤害后酒精暴露对TBI恢复和潜在机制的影响。 TBI产生的神经炎症为特征，其特征在于一系列事件，例如激活神经胶质细胞，促炎细胞因子和趋化因子的释放，内皮粘附分子的上调以及循环白细胞的浸润。我们的初步研究表明，在TBI后24小时，促炎性细胞因子和趋化因子表达迅速增加，并增强了中性粒细胞浸润到同侧损伤部位。另外，在TBI后24和72小时观察到血脑屏障的损失。持续的炎症是有害的，并导致了TBI后病理生理后遗症。酒精暴露是加重炎症的一个因素，我们的初步数据表明，TBI时酒精中毒延长了TBI后24小时的促炎细胞因子和趋化因子mRNA表达。因此，我们预测，伤害后酒精暴露将增强神经炎症性级联反应并防止炎症反应对TBI的分辨率。此外，长时间的炎症可能会导致进一步的脑损伤，从而延迟TBI后神经恢复。这是我们的初步数据支持，这些数据显示在伤害后酒精暴露的影响下神经系统恢复受损。综上所述，文献和我们的初步数据支持我们的中心假设，即伤害后酒精暴露会损害TBI后的认知和神经行为恢复。我们认为，持续的神经炎症是TBI后神经元死亡增加和神经变性受损的中心基础机制。提出的研究是作为申请人培训的一部分进行的，将使用一种综合方法来测试以下预测，即1）受伤后的酒精暴露延迟了TBI和TBI后的认知，行为和身体恢复，并且2）损害后酒精暴露会阻止神经炎的分辨率，从而使神经元死亡和破坏神经神经造成神经神经造成的神经神经造成神经造成的神经生成。拟议的研究的发现将提供科学证据，以在临床管理期间采取必要的干预措施，这可能会阻止进一步的酒精引起的次要损害以及与TBI后加速神经退行性变化相关的机制。